Jeffrey Michael Isner, MD

JEFFREY MICHAEL ISNER, MD: A Conversation With the Editor* r. Jeffrey Michael Isner was born in 1947 in Uhrichsville, Ohio, where he lived until high D school when he and his family moved to Canton, Ohio. His college was the University of Maryland where he graduated magna cum laude, and his medical school was Tufts University in Boston. His internship in medicine was at his present hospital, and his residency in internal medicine and his fellowship in cardiology was at Georgetown University in Washington, DC. After spending 2 years in the Pathology Branch of the National Heart, Lung, and Blood Institute, he returned to Tufts University Medical Center in Boston where he rapidly rose to full Professor of Medicine and Pathology. In 1988 he moved from the New England Medical Center to St. Elizabeth’s Medical Center in Boston to be Chief of Cardiovascular Research, and a few years later to be Director of the Human Gene Therapy Laboratory. Jeff Isner has been the leader of gene therapy for obstructive atherosclerotic arterial disease, and he has been a stimulus for many others to get involved in this area. His research has led to the publication of nearly 400 articles. I was fortunate to spend 27 months with Dr. Isner when he was at NIH. I knew after a short period that he was going places and certainly he has. Not only is he a splendid scientist and investigator but he also is a splendid physician and a wonderful guy. He also is an excellent story teller as this interview will demonstrate. William Clifford Roberts, MD† (Hereafter WCR): I am speaking with Dr. Jeffrey Isner in his office in Boston, Massachusetts, on July 29, 1998. Dr. Isner, I appreciate your willingness to talk to me and therefore the readers of The American Journal of Cardiology. Could you tell a bit about your early background— when and where were you born? Jeffrey Michael Isner, MD‡ (Hereafter JMI): I was born on December 11, 1947, in Uhrichsville, Ohio, where I lived until I was a freshman in high school, and then we moved to Canton, Ohio. My parents had moved to Ohio as a result of having to leave Nazi Germany. My parents were both born in southern Germany, Bavaria: my father, in a very small town outside of Nuremberg (Burghaslach) and my mother in a town called Bamberg. They had gone to high school there together but did not get married until 1940. They came to the USA in 1937. Initially, my father went to New York City, but soon moved to Cincinnati, Ohio, where there was a large GermanJewish community and where my father got a job. *This series of interviews are underwritten by an unrestricted grant from Bristol-Myers Squibb. † Baylor Cardiovascular Institute, Baylor University Medical Center, Dallas, Texas 75246. ‡ Professor of Medicine and Pathology, Tufts University School of Medicine, Boston, Massachusetts.

68

©1999 by Excerpta Medica, Inc. All rights reserved.

Some of my uncles had already moved to Cincinnati and they got a job for him. He and my mother ultimately were able to get a retail store of their own to manage in Uhrichsville, Ohio. The small town was a major culture shock for them. My parents had grown up in a fairly affluent and sophisticated environment in Germany. My dad’s family was very well off. They had a business that had been in the family for generations. Moving from there to a town in the middle of Ohio with a population of only 5,000 people with no other Jewish families was quite a change for them. Every time I had to make a change in my life I always related back to that. I thought if they could come from what they were used to and get used to starting out with nothing in an environment where they had to learn the language, the things I had to deal with were trivial by comparison. WCR: What years were your parents born? JMI: My dad was born in 1910, and my mother in 1916. WCR: Your father was about 27 when they came to the states. They had more or less grown up together I gather. What kind of education did your parents have? JMI: They both completed high school, but right at the point that they would have gone on to the equivalent of the university was the time when Jews were barred from any higher education in Germany. With all the events that happened subsequently, they never had an opportunity to attend a university. WCR: Their parents were quite educated? What did your grandparents do? JMI: Yes. I never knew any of my grandparents. They all had died before I was born. My mother’s father had a successful textile business. He died in Germany when she was 9 years old. My paternal grandfather had a large clothing business. The others all escaped from Germany. My dad was able to get them out. They came after my parents came and subsequently died. WCR: Your parents got to Uhrichsville how long after they landed in the USA? JMI: Ultimately 1946. My dad came over in 1937, received his citizenship in 1942, and was immediately drafted to go into the Army. Almost as fast as he had escaped to the USA, he was back in Germany as part of the U.S. Army in a glider division. Early on his glider crashed and he was seriously injured. When my dad went back to Germany after he got out of the hospital he was assigned to a unit that trailed Patton’s march through Europe after D-Day. He was actually assigned to a battalion that worked on securing the area he had grown up in Germany. They were taking care of the prisoners of war and one of his prisoners of war was his high school English teacher who had berated him for not learning to speak English. The 0002-9149/99/$–see front matter PII S0002-9149(99)00809-1

FIGURE 1. JMI during the interview.

teacher knew that my parents’ family was anxious to get out of Germany. Subsequently, my dad was assigned as chaplain in General Eisenhower’s headquarters and had the privilege of officiating at the rededication of the Frankfurt synagogue. WCR: Did he talk about the fact that he was a German and grew up as a German? Because he was Jewish he had to get out to survive. He came to the USA, acquired citizenship, and immediately was drafted into the US Army to fight his homeland. He must have had a great deal of mixed emotions about all that. JMI: No. I don’t think they were mixed at all. I don’t think there was any ambivalence. It was not difficult for my father and mother and other Germans in his situation to make a very quick turnabout in terms of their allegiance. They grew up being very loyal Germans. I heard the story many times about how one of my father’s relatives kept saying, “Don’t worry, there is no need to move, I have a commendation from having fought in the German Army during World War I and anybody with that particular honor was safe from persecution.” My parents being younger perhaps did not have those biases. Sometimes when you are young you can see things a little more clearly. They said they recognized exactly what was happening. My parents also were very lucky. They got out unscathed. Almost everybody in their family got out unscathed, but they were subjected to much humiliation, which had a very clear-cut impact on their thinking. I had a chance to go back to Germany with my mother about 10 years ago (My parents had always said they would never go back to Germany.) and give

a talk. I had heard so much about where my parents grew up, I thought this would be a great opportunity to see it firsthand through my mother’s eyes. We went back to her home town. A couple of things were amazing: First, when arriving she called up her former best friend whom she had not seen for 40 years. She went to the store her family had owned and the lady said, “No, she is not working here today but you can call her.” She agreed to meet my mother. My mom and I were sitting in a cafe and her friend walked in. She did not speak English so I could not understand their conversation. The amazing thing was these 2 people who had not talked to each other in 40 years, the greatest war in the history of mankind, and other unprecedented events had occurred in the interim, and they sat down and started talking like they had seen each other only the day before. The 2 of them talked nonstop for the next 90 minutes. I could not understand a word they said, but just watching the 2 of them was unbelievable. Second, my mom showed me where the Jewish synagogue had been. It had been one of the great synagogues in Germany. I had seen hundreds of pictures of it but it had burned down. There was a little stone monument where it had been. You had to look underneath all the shrubbery to find the little monument. The father of a former friend of hers, Willie Lessing, had been arrested on Kristalnacht when the Nazis burned down many Jewish synagogues. They had taken him to the middle of the square while the synagogue was burning, and they had burned each of his eyes out. They then killed him there in the square. I think when my mom and dad saw things like that happening, it was not hard to make a decision about leaving and where their allegiance was going to be. She related this story to me as we were walking along the street near our hotel when she noticed a sign saying Willie Lessing Strasse. They had named a street after him. The Mayor of Bamberg had arranged to have a tour guide show us around the city. My mom had other relatives who had been to Bamberg and the people there had tried to be very kind to any Jewish families’ returning there. When we got to the hotel there were roses there for my mother, a necktie for me, and little books about the city. The Mayor had personally made available to my mother a young German woman to show us around the city. Bamberg was spared from the bombing. It received virtually no damage during the war. It is a beautiful classic old German city. The next morning a 24-year-old, gorgeous, blond, sophisticated, well-educated, charming German woman, who spoke perfect English, arrived to take us on a walking tour of the city. She spoke to my mom in German and English. I was wondering to myself about the apparent disconnect between what is now and what was then. As we were walking along I said, “Did you ever hear of someone named Willie Lessing?” She said, “Willie Lessing, Willie Lessing, there is a street here called Willie Lessing Strasse but, you know, I really don’t know who that person was.” My mom asked what she knew about Kristalnacht. She INTERVIEW: JEFFREY MICHAEL ISNER

69

said those were the “schwarze yahren” (black years). She said she really did not know much at all about that time. This was a woman who was clearly without prejudice. She was a lovely person. She obviously had a university education and yet she knew absolutely nothing about what was happening in Bamberg and other parts of Germany during the Nazi regime. When you have heard stories like that, where people had everything taken from them, were forced to leave not just their homeland but all of their valuable possessions that meant so much to them, and saw what happened to some of their friends, it is very understandable that when my parents came to the USA, Germany was in the past and they suddenly became proud Americans. When I would visit relatives in Cincinnati, some of the older German Jews who had emigrated to the USA still spoke in German much of the time. My parent’s view was, “We are now in the USA, we are young, and this is where we are going to make our home. From now on we are Americans and there will be no German spoken in our house.” I know virtually no German at all. It was never spoken in our house. When my parents took the pledge of allegiance they knew that the USA was what saved their lives, our families—parents, brothers and sisters. We were one of those families who could not buy a German car. You did not buy German products. It was a very clear break. WCR: Your mother and daddy came to the USA at the same time? How did they actually get out? Were they able to go to another country? This was 1937. JMI: Yes. They had a pretty straightforward exit. It was difficult for them to secure the appropriate papers.

They spent a couple of years trying to go through that process, but once they did they did not have to go to any unusual measures, they got on a boat and left. The problem was that they could not take anything with them. All of their personal property that was worth anything was left behind. My mother told me about some distant relatives who had tried to be clever about that and put valuables in their trunks and got caught and paid the consequences. My parents said they wanted to leave and left everything behind. They got on a boat and initially came to New York City. WCR: They got married not long after they landed in the USA? JMI: Yes. WCR: They must have had a sponsor from Cincinnati. JMI: They had a sponsor, Sol Wetzler, my mother’s uncle, from New York; his son, Benjamin, was Chairman of the Democratic Party of New York State. My father moved to New York City first, my mother to upstate New York, and then both ultimately to Cincinnati. WCR: How long were they in Cincinnati? Your father was drafted pretty quickly after they got to Cincinnati. JMI: Yes. WCR: Was that 1942? JMI: Yes. WCR: He presumably got out of the Army in 1945? JMI: Yes. They remained in Cincinnati for a short period of time and then moved to Uhrichsville where my dad had a chance to have his own department store that he managed. WCR: How did he do after that? What kind of department store? JMI: Retail clothing. The good news was that to a large extent he was his own boss. It was his store. He did not want to stay in Cincinnati, although he had an opportunity to stay in the home office there. The jobs were pretty hard to find right after the war. Two of my uncles were working for a clothing company and my dad asked if he could go to work with them one day. He said he had nothing else to do. They told him that there was no job for him. Nevertheless, he went to work with them. Not having anything to do he walked into a room and started straightening things up. Suddenly, the owner walked in and asked what my dad was doing there and my dad said he had nothing else to do so he came to work with his brothers-in-law, found the room a mess, so he started straightening it up. The owner shook his head and gave my dad a job on the spot! My dad, however, wanted to be his own boss. To do that he had to move to Uhrichsville, Ohio, where he had his own store and some independence. When I was growing up I thought we were rich. There was never a time when I wanted for anything. We had a great family. My parents went out of their way to make things comfortable. My dad never made a lot of money during his life. He was paid very modestly. In retrospect, I now realize that. As kids, we had a great time. My sister and I thought we had everything we needed.

70

JANUARY 1, 1999

FIGURE 2. JMI during the interview.

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

JMI: Yes. Both mom and dad worked in the store. WCR: So that is how she was able to become manager? JMI: Yes. WCR: What was it like at home? Did you discuss events of the day or your class work at dinner in the evening? JMI: First of all, it was an incredibly nurturing environment. For my parents, the family was absolutely everything. Kids were everything. Every time I ever met anyone who was a friend of my parents from as early as I can remember, the first words out of their mouths were we have heard all about you from your family. My mom had a hard time getting pregnant so by the time they had a couple of children they really felt lucky. WCR: They got married in FIGURE 3. As an 11th-grade participant in Canton, Ohio High School Science Seminar, JMI 1940 and you were not born un(left) and classmate review cineangiogram performed earlier that day by Dr. Grace Hoftil 1947? steter (center). JMI: Yes. They were both incredibly loving and generous people. I thought everybody was like that until I went WCR: What year did your dad die? JMI: He died in 1976 when I was a first-year car- away to college. I never really understood how exceptional it was until I started to meet friends and saw the diology fellow. other options. Above all, they had an unbelievable WCR: Is your mother still living? work ethic and they imparted that to my sister and me. JMI: Yes. Because what had happened to both my parents’ havWCR: What is her age now? ing to start from scratch after coming to the USA, JMI: Eighty-two. WCR: What has happened to your mother in these although they never complained, my dad and mom were insistent we get an education so that no matter last 23 years? JMI: She managed the department store after my what events occurred around us we had something that dad died. My parents wanted us to move to a city that was exportable, something you could take with you had a larger Jewish population and better schools so that nobody could take away from you. A lot of our we moved to Canton when I was a freshman in high discussions at night were what we did in school? What school. My dad had scouted out the area and found a did you learn? Because they had been subjected to this place that did not have one of the stores and he cataclysmic Holocaust they were also very much convinced the guys in Cincinnati to open another one tuned into everything happening in the world politiin Massilon, Ohio, near Canton. Massilon is big foot- cally. My dad went to his grave honestly believing ball territory. That is where Paul Brown used to coach that President Franklin Roosevelt had intervened perhigh school before he went on to coach the Cleveland sonally to get his parents out of Germany. My dad had Browns. After my mom retired from managing the written hundreds of letters to Roosevelt to try to get store, she moved to the Washington, DC, area where his parents out while they were exploring all kinds of other avenues. When my grandparents actually got my sister and I were living. out, my dad was convinced it was because Roosevelt WCR: There were 2 of you, you and your sister? had personally intervened. There were a lot of discusJMI: Yes. sions about politics and world events. WCR: You are the oldest? JMI: Yes. WCR: When you grew up you were not around other family members? They were in Cincinnati, WCR: You were born in 1947, and your sister? Ohio? How far was Cincinnati? JMI: My sister was born 3 years later (1950). WCR: Although your mother and father were not JMI: A 3-1/2 hour ride. In those days people did not able themselves to go to college it certainly sounds fly so much. like they grew up in an educated family. It was just WCR: The relatives you knew in Cincinnati were this unfortunate circumstance that prevented their go- not your grandparents? ing to college. What was home life like in Urichsville JMI: Correct. They were aunts and uncles on my and Canton? Did your mother work? mother’s side. INTERVIEW: JEFFREY MICHAEL ISNER

71

WCR: So you knew nobody from your father’s side? JMI: My father had one sister and she lived on Long

Island. We visited her family there on occasion. WCR: What was the population of Uhrichsville? JMI: About 5,000 people. WCR: Canton was how far away? JMI: Forty-five minutes. WCR: What was the closest biggest city to Canton? JMI: Cleveland, about 90 minutes away. WCR: So you went to Cleveland periodically? JMI: We would go there to watch baseball or football games. WCR: Your school work was considerably well supported at home. I presume that you did extremely well academically in junior high and high school. Did you play sports? JMI: I played a lot of sports as I was growing up but I was never really good enough to make any of the school teams. That area was a hot bed of football in particular. Most time outside of school was spent playing sports. My father was a musician and had a great voice. He was a part-time cantor in a Jewish synagogue in upstate New York where we went once a year. It was a small community where one of my mother’s brothers lived. The synagogue was not large enough to require a full-time compliment of cantor and rabbi throughout the year so my father would go once a year for the high holidays as the visiting cantor. He really loved music. My sister and I were never that receptive to it. We took piano lessons and trumpet lessons. I played in the band but I always preferred to be involved with sports. My parents were dead set against it. I wanted to play football and I was big enough and could have played. When we were growing up, one year I begged them to get me a football outfit. What they did was give me the whole outfit except the helmet. I think they figured I was smart enough not to go out and play without the helmet. They were not very supportive from that side of things. That was the only negative about my parents. As you know, I had a lot of interest in sports so I converted that to being a sports writer in high school and college. WCR: You wrote for your high school newspaper? JMI: Yes. When I got to college I was the associate sports editor of our college newspaper. WCR: Did anybody other than your family have much of an impact on your growing up? JMI: My mother and father had such a great impact and I regarded them with so much respect that it took a lot for anybody else to make much of an impression on me. They were so honest and hardworking. As a child and still to this day, I never saw any negative qualities about my parents. Thus, I always looked at other people by how they measured up to my parents. I don’t remember any adult figure who had much of an impact on me until I was in high school. In Canton, Ohio, they had a thing called the science seminar. The 4 high schools there organized this for students who excelled in science courses. It was structured so that every month they would have 50 to 60 students from the 4 high schools get together, and they

would have speakers from different professions every month discuss what they did. After 6 months, each student was supposed to select someone as an advisor or mentor and go to where they worked and learn what they did. One speaker was a cardiologist, Grace Hofsteter. By the time I was in high school I was inherently curious about biology and already knew I wanted to be a doctor. There was a history of heart disease in my family. That is probably why I was always particularly curious about cardiology. She gave one of the talks and she was a wonderful woman. I talked to her about hooking up with her and she allowed me to do that. She was Mason Sones’ first cardiology fellow at the Cleveland Clinic. There were a handful of women who did cardiac catheterization procedures at that time. She set up the first catheterization laboratory in Ohio outside the Cleveland Clinic. She had a great interest in pediatric cardiology as did Mason Sones. I would go out to Timken Mercy Hospital (where her cath lab was) every Wednesday after school. I watched her do cardiac catheterizations and then follow her around. It was oftentimes children or babies. (This was before the days of coronary bypass surgery.) A lot of it was valvular heart disease and congenital heart disease. With so few cath labs she had a large catchment area to draw from. I probably saw more pediatric cardiology during that year and one half than I saw in my entire career in cardiology. She would go over the angiograms with me and take me to see the baby and show me something on physical examination. There were occasional patients with coronary disease. I spent every Wednesday doing that. This was when I was in the 11th and 12th grades. At the end of the science seminar you had to write what amounted to a paper or thesis. I spent a lot of time during my senior year in high school trying to work my way through books on congenital heart disease. I would go to her and ask her questions. In retrospect, when I think about how underpowered I was to try and understand any of this material, it is almost ludicrous, but I did learn. I still have this little paper that I wrote about tetralogy of Fallot, transposition of the great arteries, pulmonary atresia, etc. My job at the final meeting of the science seminar, along with the other students, was to give a 20-minute talk about what we had been doing. I practiced this talk at home the night before with my parents. I got to the end of it and my dad had this like glazed look in his eyes. I asked, “What do you think?” He said, “Jeff, I don’t understand a single thing you said but it was the greatest talk I’ve ever heard.” Those meetings with Grace Hofsteter had a really major impact because she subsequently arranged for me to get a job working summers at the Cleveland Clinic for Mason Sones as his personal “gopher.” In addition to that, she had an important impact on my choice as to what I was going to do. Most important of all, she was and is the most compassionate, honest, hardest working, best physician I have ever met in my entire career. For a long time she was the only cardiologist that Sones or any of the other staff at the Cleveland Clinic would accept catheterization films

72

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

from without repeating the study before operation. Anytime you met anybody from the Cleveland Clinic and asked about Grace Hofsteter it was amazing the respect they had for her. She came from a Quaker background. Her sister was a missionary in India. The 2 of them were the most humble, self-effacing people I have ever met. She, to me, is still the model of what a doctor and certainly a cardiologist should be. WCR: Did you go up to her after her talk and ask if you could follow her around? JMI: Yes. I said I would like to see what you do and I am interested in going into medicine and being a cardiologist, although I don’t really know what that meant. It would help me a lot to see what you as a cardiologist actually do. She was really happy to do it. She was incredibly generous with her time and everything else for the rest of my life. WCR: Were you and your sister close growing up? JMI: Yes. We have always been close. WCR: What does your sister do? JMI: My sister became a nurse and went on to get her masters degree in nursing. She was, for a period time before she had a family, working as a hematology oncology nurse at Georgetown University Hospital. More recently she has gone back to working in a radiology/oncology group associated with Georgetown. She has done very well. When I went back to do my fellowship at Georgetown and she moved to Washington, one of the people we had grown up with in Canton, Ohio, Bob Meister, was doing his residency at Georgetown. He introduced my sister to one of his fellow residents and he became her husband, Dick Robinson. WCR: What other activities in high school did you participate in that may have had an influence on you? JMI: When I was a junior in high school and became 16, I had to get a job. Both my sister and I had to work to have spending money. I got a job working as a carry-out boy at one of the local supermarkets. The job had an important impact on me. Early on, one of my first responsibilities was to clean the floor behind the meat counter after the store closed. This involved picking out all the meat that got stuck in the holes in the meat mat so that it would be clean the next day. I then had to clean out the toilets in the restrooms. After about 2 nights of that and after spending 8 hours on a Saturday carrying out groceries all day, just looking at the clock from the minute I got there until the minute I left, I said to myself that I had to be able to do something that I really loved for a job, because I could never ever spend the rest of my life wishing away the hours of the day. I thought about how people spend their entire lives working at jobs where they basically can’t wait to be out of what they are doing. I thought that no matter how hard it might be, I had to do something that I loved. WCR: So that experience was a great stimulus to make you work hard in your studies. JMI: Yes. WCR: It sounds like you could have played sports, but that was something your parents knew did not have much of a future for you.

JMI: Yes. That is a very nice way to put it. WCR: They sort of steered you to other paths. Is

that proper? JMI: I think my wife would probably be a little more blunt about that, but I think that is accurate. WCR: Jeff, how did you go to the University of Maryland to college? JMI: This is going to be hard to believe. Both Dr. Hofsteter and Sones had gone to the University of Maryland Medical School. From both of them I heard about the University of Maryland, and so I decided that it was a place I was going to at least visit. Growing up in northeastern Ohio is nothing like living in Boston, where parents talk from the day the kids are born about what is the best Ivy League school their kids can get into. I did not know that much about Ivy League schools. Half of the schools I found out about when I went to medical school I had never even heard of before. I was naive about that. Where I went to school everybody was interested in football. I knew about every school in the country that had a good football team. Dr. Hofsteter and Dr. Sones talked me into visiting the University of Maryland. The medical school was in Baltimore and the undergraduate school was in College Park, Maryland. They had nothing to do with each other. My dad and I went up there. The place was one of the most beautiful campuses I had ever seen. It was a big school even at that time, about 27,000 students. I knew one of the kids there on the football team who was from close to where we grew up and I went to see him. He showed me the stadium and told me what a great time he was having there. We went there for what was supposed to be the interview. The lady told me there was almost no point in going through the interview because they took so few outof-state students. I said I would take may chances and had the interview. Right after that I came out to the car where my dad was sleeping. He asked how it was and I told him I didn’t know because they said they did not take many out-of-state students. I said it might have been a waste of time. He suggested we go see what Washington was like. My dad had gotten us a hotel room to stay overnight in Washington, DC. That was the first time I had ever been to Washington, which was about 15 minutes from College Park. I thought it was the most spectacular place I had ever been—the White House, the Capitol, the Washington Monument, Arlington Cemetery. At that time they were building the Kennedy Center. I thought this was a great campus, a great football tradition here, 15 minutes away from a great city; what else did you need? The other thing was that I knew I wanted to go to medical school, and I knew that I was going to have to work hard to get into medical school because it was obviously very competitive. My thinking was that if I was going to have to work hard to get into medical school, then if I am going to have fun the fun has to be right there. I am not going to have time to go searching around for it. Here was a beautiful campus with 27,000 people, hundreds of great looking girls. I thought that would be a pretty INTERVIEW: JEFFREY MICHAEL ISNER

73

good combination. My choice of a college was a little crazy but that is the way it happened. Those were 4 years of my life that I would never ever trade for anything in the world. If I had to go back and do it over again, knowing a little more now than I did then, I would not change that decision for anything because I had a great time, made great friends that are still my best friends to this day. I grew up a lot socially and I grew academically as well. I was also sports writer for the school newspaper. WCR: Had you graduated first in your class in high school? JMI: I was 4th or 5th in my class of 200 students. WCR: When did you hear that you had been accepted at the University of Maryland? JMI: I think it was in the late winter or early spring in my senior year in high school. WCR: The number of students at the University of Maryland was 5 times larger than the town you grew up in. Canton had how many people? JMI: About 100,000. WCR: You mentioned you were a sports writer for the college newspaper. Did you do that right away or how did that come about? JMI: I was very lucky there. I happened to meet a couple of guys soon after I got there and joined a fraternity. Most in my fraternity were from out of state. There were not many people at Maryland at that time who came from out of state. We were all strangers in a way. This was a way to bond together. One guy who was a senior in the fraternity and was working for the school newspaper got me a job on the school newspaper covering varsity baseball and freshman basketball. I did that for a year and then got the job covering the varsity basketball team. Maryland’s basketball team was not good in those days, but they were in the Atlantic Coast Conference so I got to go to every Atlanta Coast Conference (ACC) tournament during my sophomore, junior, and senior years. I had the same press credentials that the reporters from The Washington Post and Baltimore Sun had. I would sit there right beside Ken Denlinger from The Washington Post and the guys from the Baltimore Sun. It was a great “Walter Mitty” fantasy. I could pretend that I was a real genuine sports writer. At that time, Frank McGuire coached South Carolina; Vic Bubas, Duke; Dean Smith, North Carolina; and Norm Sloan, North Carolina State. I had the license, by virtue of the press pass, to go up and ask any of these guys anything I wanted. It was a great thrill. When I was a senior one of my best friends had gone to high school with the son of the athletic director. We were sitting at the fraternity house one night and he said he had just talked to Jimmy Kehoe and he told me that his dad was going to announce the next day that Lefty Driesell was going to come to the University of Maryland from Davidson to be the head basketball coach. I ran back to the Diamondback (the name of our newspaper) office, and I called Lefty Driesell’s home in North Carolina. He answered and I said, “This is the Maryland Diamondback calling and we want to confirm that you are going to be an-

nounced tomorrow as the next head basketball coach here.” He started laughing and said “What, where did you hear this?” I said I could not reveal my source but I asked if he could confirm that and he started laughing again. He said, “No, I can’t confirm that.” I said, “Will you deny it?” He started laughing again and said, “I can’t deny it either.” I said, “Okay, we are going with the story tomorrow morning that you are going to be announced as the next coach here. Is there anything foolish about doing that?” He started laughing again and said, “You are getting me into trouble and I had better not say anything else.” The next morning we ran the headline story on the front page of our school newspaper that Lefty Driesell was coming here to be the head basketball coach. This was the ultimate “Walter Mitty” episode. The next day, I was sitting there in the Diamondback office and I got calls from The Washington Post and Baltimore Sun, asking us how we had scooped them! WCR: So you wrote regularly during the basketball season? JMI: They played 27 games. I wrote almost daily about the team and then every night after the game I had to put a story together for the next morning about the game. I also was one of the writers covering the football team. WCR: So when you were in college, you wrote a lot of sports columns? JMI: I did, including one based on an interview with Red Auerbach. He was living in Washington when he was with the Celtics and he would come over and watch a lot of the basketball practices at Maryland. I got to interview him for about 2 hours and he was terrific. WCR: By the time you finished 4 years of college you knew how to produce an article quickly. JMI: I learned how to do that. I was not good at it initially. I am not a fast writer and I was slow initially. I got some lessons pretty quickly on how to do it faster. WCR: You got a degree in practical journalism? JMI: Yes, you could call it that. Interestingly, one of the other people on our newspaper at that time was Connie Chung. She was a year ahead of me. She, of course, was not doing sports. WCR: So that was a wonderful experience for you. It must have taken a lot of time to go to every one of those games, to write an anticipatory article before a game, describe the game, do interviews, etc. JMI: It took a lot of time, especially for a premed student. A lot of the students who were on the paper were journalism majors. This was part of their classes almost. For a premed student it was tougher. One of the most stupid things I ever did in my life was this: Maryland had the first black basketball player to play in the Atlantic Coast Conference. I came to college in 1965 and that year a black basketball player named Billy Jones started playing in Maryland, the first one in any of the ACC schools. I thought it would be good to do a story on what it was like to be the first black basketball player in the ACC, because when he went to North Carolina and South Carolina he had to put up

74

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

FIGURE 4. Photograph of JMI’s fellows at Saint Elizabeth’s Hospital, Boston.

with a lot of guff and it was not easy for him. He was a great guy. I was so pressed for time, however, that instead of saying, “Let’s go out and have a beer or let’s sit down in the locker room after a game,” the best way to do an interview, I called him from one of the pay phones on a Sunday night while I was studying at the library and said, “Hey Billy, this is Jeff Isner and I would like to talk to you about what it was like to be the first black basketball player in the ACC.” You could imagine what a productive interview that was! It was the consequence of not having a lot of extra time. WCR: What did you major in college? JMI: Zoology. There were a certain number of required courses that you had to take as a pre-med student. It was a pretty rigorous and structured premed program. By the time I had taken all the required courses I had only to take about 2 more zoology courses to have a major in zoology. To be able to take some non-science courses, like art, history, music, and literature, I wanted to get the science major the most efficient way and zoology was the answer.

WCR: It sounds like you were very busy in college. You were a member of a fraternity. You mentioned girls. Your social activities were pretty active. You were going down to Washington periodically. You were doing the newspaper column. I guess you kept all those columns? JMI: Yes. I still have a scrapbook. WCR: That was wonderful training for what you do now and have done in your professional career. JMI: There is no question about it. It really forced me, particularly that kind of writing, to be very efficient. I had a great high school English teacher, Esther Smith, who was one of the few teachers I still remember from either high school or college. She taught how to organize a coherent piece of writing. That was important to me. In college, writing with a deadline made me efficient, not only in how fast I could do it, but also in a limited amount of space. I am not saying this just because you are interviewing me, but the person who really taught me how to write was you. When I would sit there in your office the way you used to do it, I would bring in a draft and you would INTERVIEW: JEFFREY MICHAEL ISNER

75

basically tear it apart and start from scratch. I watched how you put words together and how you edited things. That had a critical impact on my ability to write. WCR: Did some of your fellow students (you talked about great friendships you formed in college) have a significant impact on you? You said that still to this day they are your closest friends. JMI: One of my best friends, Bob Pincus, became the president of two banks in Washington. He was very successful, although no one would have predicted that on the basis of how he performed in college. My best friend in college and roommate for 4 years was Larry David, who subsequently became the co-developer, co-producer, and chief writer for the Seinfeld show. He and Jerry Seinfeld originated that show. I thought about this a lot after he won his first Emmy. When we were driving down to Florida for Spring break 1 year, there were 4 of us in the car, Larry, myself, 2 other guys. One of the other guys, Corey Blechman, also won an Emmy for writing the screenplay for Free Willy. I was thinking what were the chances of being in the car with 2 guys who ultimately go on to win Emmys? There were obviously some really creative people in our group. When I went out to visit Larry when the American Heart Association was held in Anaheim, Jim Symes (our Chief of Cardiovascular Surgery), Marianne Kearney (my chief technician), and I were given “walk-on” roles for one of the Seinfeld episodes. Larry had previously spent a number of years doing standup comedy in New York City before he wrote Seinfeld. When I was working and living the life of an intern, feeling like the lowest person on the totem pole, one weekend I went down to visit Larry and he was living in a rundown apartment near Times Square. He was doing standup comedy with Robert Klein and others. He performed every Saturday night. I tagged along with him. He would go into 1 club and they would say “Oh, Larry, great to see you. We will get you on in about 5 minutes.” He would wait and all of sudden someone else would walk in and Larry would not get the performance. By the time Larry would get on it would be about 12:30 A.M. and then no one would be there but a bunch of drunks. To go through that kind of rejection night after night made my life as an intern seem like a piece of cake. WCR: What did your parents say to you when you would send the newspaper columns home to them? JMI: They thought it was the greatest. If it had been up to my parents they would have been at the University of Maryland every weekend. They worked so hard to make sure their kids could go to school, and, frankly, that was another part of going to Maryland. My parents were in a financial situation where it was not so easy for me to qualify for a scholarship, but, on the other hand, if I went to a school that was more expensive it was going to be an incredible stretch for them. It turned out that Maryland was less expensive as an out-of-state student than going to Ohio State would have been as an in-state student. When I looked at that, I thought it would be a good deal for my

parents, and, if I worked some, it would not be too tough for my family. They, as a result, wanted to hear every single detail about what was going on at the college because that was what they lived for, to send their kids to school. WCR: Did you have an automobile in college? JMI: No. I think I was probably the only kid in my fraternity that didn’t. I never had a car until my senior year. I remember coming home at the end of final exams my junior year. My dad came to pick me up at the Cleveland-Hopkins Airport. I was exhausted. I just wanted to get to sleep and my dad took me out to this car, and I said, “Geez Dad, this is not your car.” He said, “No, it’s yours.” I finally had a car my senior year! WCR: You made Phi Beta Kappa in college your junior year? JMI: Yes. WCR: You graduated magna cum laude? JMI: Yes. WCR: What does magna cum laude mean at the University of Maryland? JMI: I think it was based on your grade point average. WCR: It sounds like you worked extremely hard in college. You wanted to do well and your mission was to get into medical school. The sports writing sounds like it was something that after awhile you could not turn down. You could not give it up because it was providing too many opportunities and fun things. You were meeting people. You must have had a busy life in college. Did you sleep much? JMI: No. I remember coming home from the library when it closed at midnight. There was a sub shop where you would stop off to have a sub when you were getting ready to go to bed. Then you would come back and sit around with the guys before going to bed about 1:00 A.M. I was 1 of the few people in that fraternity who got up for an 8:00 A.M. class. Larry was my roommate and he never went to class. I was one of the few premeds in this fraternity and people always asked why I was studying so much? WCR: You lived in the fraternity house?

76

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

FIGURE 5. JMI performing intramuscular gene transfer for the first time in a patient with severe peripheral arterial obstruction.

JMI: Yes. I lived there until my senior year and then had an apartment off campus. WCR: Did anybody have an impact on you in college? It sounds like the college newspaper was very influential? What about teachers? JMI: When I look back on it, I don’t know that there was any teacher that had a major impact on me. I knew I wanted to go to medical school so I did not need any kind of stimulus to study. I knew I had to get really good grades. One course which had an important impact on me was our honors course in science and philosophy that I was selected to take. That was perhaps the first time I ever encountered a truly Socratic type of teaching. We met at the professor’s house. It started making me understand that there was a different way to think and approach things. We also had a good English Department and I read a lot of Southern writers like Falkner and Ellison. That was a great reprieve from all the science. I still have the books we had to read. I read relatively slowly, but part of that was due to my studying the author’s writing technique as well as the content. That helped later on in terms of being able to write. WCR: How did you pick Tufts University School of Medicine? JMI: This was about as insightful as the way I picked Maryland to go to college. I loved being in the Washington, DC, area and I thought I wanted to be a practicing physician in that area. I wanted to go to Georgetown Medical School in Washington, DC. I applied to Georgetown and got in right away. I also had sent an application to the University of Maryland Medical School in Baltimore. I was asked to go to Maryland for an interview. I got to Baltimore a little bit late for the tour they were giving the interviewees. I was trying to find out where the tour was when I ran into the brother of one of my roommates at the University of Maryland who had just started his freshman year there. (He subsequently went on to be a very successful orthopedic surgeon in the Washington area.) He asked what I was doing there? I said I was there for an interview because I had applied to medical school. He asked if I was crazy, otherwise why would I want to spend 4 years in Baltimore. He said he was there because he had to be there. He said I could get into a lot of places. He said he had been in Boston the week before riding the MTA with a friend of his and that he must have fallen in love 15 times. He said if he were me that he would go to Boston to medical school. I wrote to Tufts and asked if it was too late to apply, and they said there was another month so I applied. I had never been to Boston or New England. When I went to visit Tufts, one of the things they did on the tour of the medical school was to allow us to spend an hour with a former fellow of Dr. Proctor Harvey’s, Dr. “Chris” Chrisitiello. The stethoscopes were set up and we listened to heart sounds. It was just by chance he happened to be doing it that day when I was there so I thought this was great since I wanted to go into cardiology. I was interviewed by one of the Associate Deans, Norman Grace. (He now has a place close to ours at the Cape, so I see him every weekend

there.) I don’t remember much about the interview except that he asked what I imagined myself doing several years later. As a typical college student, I usually was thinking a maximum of about one day in advance. Certainly, I never got more than a year in advance. My role model as a doctor was Grace Hofsteter, a practicing physician. I said to him, “I don’t know. I have not really thought that far in advance. I would be thrilled to get into medical school and I imagine that there are a lot of things you can do as a doctor and I am willing to consider all of them. The only thing I can tell you for sure that I have no interest in is academic medicine.” WCR: Did you get a partial scholarship? JMI: Yes, and it was very partial. Tufts, even at that time, was one of the more expensive medical schools. I also got a very large loan. The only way that I would go to a place like Tufts was if I got that loan because I was very certain that I did not want my parents to have to pay for anything in medical school. I could have gone to Ohio State Medical School which was a lot less expensive, but I figured I would go to Tufts if I could get a combination of a scholarship and loans, so my parents would not have to pay for anything. I was able to ultimately pay for all my medical school. In those days there was a really great loan program. I worked all the way through medical school as a bartender and a waiter at a couple of the local pubs to make some extra money. WCR: Medical school was just like college for you. It was not the only activity you were doing during those 4 years. JMI: The only difference was that you really had to work at it to make sure it was not the only activity. It was very much different from college in the sense that all of a sudden you walked into a class where there were 120 clones of yourself. In my fraternity, I was one of the only premeds there, so everybody was doing something different from what I was doing. All of a sudden everybody was doing exactly the same thing. That was weird, and, moreover, all of a sudden from morning to night, all you studied was science. It was very monolithic. I took advantage of what was, at that point, a very liberal time at Tufts Medical School. This was during the Vietnam War. It was when a lot of universities and medical schools were starting to experiment with the pass/fail system. Tufts was one of the earliest to have a pass/fail system. I am not proud to say that I took full advantage of that. I was fortunately able to take a number of art courses and music courses at Harvard’s night school just to do something different. Nevertheless, I could say that the first 2 years of medical school were probably the 2 least enjoyable years of my entire academic learning experience or career. The first year I was there we had one of the worst snow storms in the history of Boston. All of sudden, around November I thought I was in Siberia. It always snowed. I went to the medical library and got the names of 5 medical schools in southern California and actually wrote applications to transfer. It was also compounded by the fact that I barely had INTERVIEW: JEFFREY MICHAEL ISNER

77

enough money to do much. Everybody I had graduated with at Maryland now had jobs and most were having a great time. They had enough money to enjoy themselves. Here I was 22 years old, living in a 2-man dorm room with hardly enough money to date. It was just not that much fun. Once we got into the clinics and started doing what I thought you came to medical school to do, however, then it became more fun. I then began spending more time going back and looking at material I learned in the first 2 years, since you could now see certain basic elements fit into what you were doing clinically. Then, as opposed to the first 2 years, I developed a voracious appetite for it. WCR: You obviously did not follow through on your applications to southern California medical schools. JMI: Probably inertia more than anything else. Once the Spring came and the snow melted and I could see signs of life it was different. I had a few good friends by then and we rented a place together for the next year. It seemed like I should stay. WCR: You worked harder the last 2 years than the first? JMI: Much harder. WCR: Who had an impact on you in medical school? JMI: The person who had the greatest impact on me in medical school was not on the faculty at Tufts, but was Mason Sones at the Cleveland Clinic. For 3 years I went back and worked directly for him in the summers. I was his personal gofer. He was such a unique guy, although always very controversial. People had very strong feelings regarding him one way or the other. To me he was the greatest. He was first of all one of the most honest people I have ever met. He was honest to a fault. There was not an ounce of “BS” about him. I just instinctively appreciated the fact that he was so very authentic. There was no agenda, no program—what you saw was what you got. Not only that, but 1967 was the first year I was at the clinic and that was the year that Rene Favalaro did the first coronary bypass operation. All of a sudden the whole face of 20th century cardiology completely changed. I was there as a premed and then a medical student— just awestruck by these gigantic first steps. I spent a lot of time in his office while some of the major figures in cardiology (At the time I did not know who they were but later on recognized the names.) were coming in there and I would sit there and watch and listen. Even as a totally unimportant, irrelevant medical student, Sones would spend an enormous amount of time with me. I would sit there at night and watch him go over angiograms. If anyone looks at enough angiograms, you can start figuring out what is going on. That was the time they were switching from doing the Vineburg procedure to coronary bypass. Soon I was comparing every other doctor I met to Sones. It was hard to find people who were achieving or changing medicine as much as he was. Frankly, it was hard to find people who were as unpretentious, down-toearth, and brutally honest as he was. For better or worse, Sones was the man who I ended up comparing a lot of my Tufts faculty to.

There were also people like Louis Weinstein who at that time was at the peak of his career. No matter what rotation I was ever on, I always tried to get over to go to his rounds because they were classics. He was a very inspiring figure. John Harrington, who at that time was one of several young outstanding nephrologists at the New England Medical Center, was very energetic and popular with the students. He took lots of time with the students. He is now the Dean of the Medical School. He encouraged me to keep academic medicine as a career option. And my cousin, Welton Gersony, also encouraged me to do an elective at Columbia-Presbyterian (Baby’s) Hospital in New York City, where he was and still is Chief of Pediatric Cardiology. He made a very important impact on me. WCR: So you never changed your mind during medical school as to what you wanted to do. You wanted to be a cardiologist from those high school days? JMI: Right. I did, however, go through a period when I wanted to be a psychiatrist. Tufts had a great psychiatry department with a lot of young terrific guys. We had a lot of exposure to them during the first 2 years of medical school. That was the bright spot during the first 2 years of medical school. First of all, there were a lot of elements of English and history and drama. The psychiatrists would use all of that as part of their teaching. I loved that part of it. I spent 1 summer taking an extra elective in Boston doing psychiatry. One of the faculty helped me get a summer job at St. Elizabeth’s Hospital in Washington, DC, doing psychiatry as part of the U.S. Health (“CoStep”) Program. I had a great mentor there named Steve Pechynic. When I had discussions with Sones about what I was going to do and I would tell him I wanted to be a cardiologist like he was, he said to me, “I think this is the frontier of cardiology, a great time to be a cardiologist, but it is not always going to be this way. I suspect that you should go into an area where people don’t know anything. You ought to go into psychiatry. Those people are clueless. That is what I would do if I were your age.” I spent a lot of time in psychiatry. I even went to London, United Kingdom, to do an elective at the Maudsley Hospital. I really thought, to my parents’ great anxiety and concern, that I might be a psychiatrist! WCR: You got that out of your system by the time you entered the wards? JMI: Not entirely. I thought that I would take at least a year of medical internship, because even if I thought I was going to be a psychiatrist I thought it was important to do that. My desire to be a psychiatrist ended after I started my internship. I really loved the medical internship and from then on I knew I would be a cardiologist. WCR: How was class standing determined at medical school on a pass/fail system? Do you have any idea? Where did you stand? JMI: I have no idea. I guess the written evaluations were such that they ended up determining where you stood in your class but I had no idea where I was in my class.

78

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

also worked during those 4 years. How many hours were you working a week? JMI: Probably 16 hours a week as a waiter or bartender. WCR: That is a lot of time while in medical school. When you were doing your internship I gather this is when you really decided you liked medicine, you liked being a doctor, and the internship was the hardest you had worked up to that point in your life. Who had an impact on your during the internship? JMI: My peers. It was a very strong house staff at that time including my own group. One of my colleagues and best friends, Barry Benowitz, went on to become an endocrinologist at the University of Utah; and a year ahead FIGURE 6. JMI and wife Linda with sons Josh (center), Matthew (right), and daughof me, Mike Jaker and John Dowling. ter Jessica (left). Mike Jaker went on to be on the faculty at the New Jersey Medical School. John is now my personal physician WCR: You are an athletic-appearing person. Did and he also takes care of my friends, wife, and in-laws. surgery appeal to you at all? He is now here on the staff. He gets an award every JMI: What I loved about surgery was the locker- year for being one of the best physicians in Boston. I room atmosphere. I loved the fact that you would go learned a lot from them. I still remember vividly into the operation saying “let’s go get ‘em.” You specific patients where these guys would drill me would come out and say “That was great, let’s go out because there was something I did not know or had and have a beer.” Part of it was terrific. The camara- not thought about. I can still remember walking with derie of the surgical team anytime of night, the Mike Jaker down one of the corridors that I now walk tougher the better, the worse it got, was great. That down every day talking about the differential diagnopart of it still appeals to me. Maybe that’s why inter- sis on a patient we were going to see in the emergency ventional cardiology appeals to me. What was miss- room. They were enthusiastic, great teachers, just huning, however, was the differential diagnosis. I don’t gry to be on the front line. There were plenty of sick want to say that internal medicine is more intellectual patients to take care of. The guys I was working with than surgery, but it was a different way of looking at every day and every night were the ones I really things. The real deal in surgery was to do great surgery learned a lot from. and less emphasis on the intellectual exercises of The attending staff included Bernie Kosowsky, internal medicine. I liked that about internal medicine. who had just become Chief of Cardiology. He took One of my best friends in medical school, Chip Glass- over from Tom Ryan who had just left to go to Boston man, liked both surgery and medicine. He liked the University Medical Center. At that time his major operating room/locker room atmosphere even better interest was cardiac arrhythmias. He had worked with than I did. He went off to be a urologist. Tony Damato at Staten Island and also with Proctor WCR: Why did you pick St. Elizabeth’s Hospital for Harvey at Georgetown. He spent a lot of time with your medical internship? medical students and house staff on arrhythmia interJMI: A combination of things. I had made friends pretation and physical diagnosis. That was, of course, here. I had worked at St. Elizabeth’s while in medical appealing to me as someone who wanted to go into school because it was one of the Tuft’s teaching cardiology. He pushed hard for me to go to Georgehospitals. Some of the best times that I had had while town. Ken MacDonell, who at that time was Chief of I was in medical school were spent at St. Elizabeth’s. the Pulmonary Division and Director of the Intensive It was an unusual hospital because there was a full- Care Unit and is now the Chief of Medicine, simply time academic faculty, and at the same time a large made it fun to be a doctor. When I was a student and cadre of physicians who were in private practice. We took an elective with him here, he would grab a bunch saw large numbers of patients with myocardial infarc- of students and take us over to hear the clinicopathotion, pneumonia, sick-as-hell diseases, and at the same logic conference at the Massachusetts General Hospitime there was still a very academic approach to how tal, or if there was a great speaker anywhere else in you took care of these patients. It was a great aca- town, we would go hear the talk. People like Ken demic environment to learn how you take care of very MacDonnell genuinely enjoyed practicing medicine. sick people. It was authentic and genuine. Not surprisingly, they WCR: When in medical school you paid your own were great teachers. They also made sure that anyway and what you could not pay you borrowed. You thing you said you could back up with data. There was INTERVIEW: JEFFREY MICHAEL ISNER

79

also Bob Flynn who was Chief of Neurology and subsequently became Chief of Medicine. He later became Director of Caritas Christi, the network of hospitals that St. Elizabeth’s is part of. He was a spectacular neurologist. Rotations through his neurology division as well as Ken MacDonnell’s pulmonary division were 2 of the most popular rotations at Tufts Medical School. Bob Flynn was a great teacher, a great diagnostician, and a very tough guy who would not put up with any BS at a time when long hair was in style. He was a great role model. Fred Stohlman, who was Chief of Medicine at that time, had just come from the NIH. They created a research department for him. He was the Editor of Blood. He had done seminal work on erythropoietin at NIH and had established a strong research group here in hematology. One of the young guys he had was Peter Quesenbury who was my very first attending here. He was a dynamic guy, hard core in the best sense of the word. He never stopped rounds when the clock stopped, but only after he had seen every patient. He would thoroughly discuss every differential diagnosis. He referred to every relevant article. When he was an attending, that is what his life was for that month. He was a tremendous teacher and subsequently went on to become Chief of Hematology at The University of Massachusetts Medical School. Lou Braverman, who was Chief of Endocrinology, was one of the editors of the major endocrinology textbook, and he also is now at the University of Massachusetts in Worchester, where he became Chief of Endocrinology. They were all outstanding teachers and physicians. At the end of that year, I knew reflexively how to deal with any patient that came across my path. WCR: You were very pleased at the end of your internship in the choice you had made? JMI: That year was one of the very best years I’ve ever had. Shortly after I finished the 2 years with you at the NIH, I came back to St. Elizabeth’s to give Grand Rounds. I got up and said, “I know I am going to lose all credibility by saying this but the year of internship I spent here was 1 of the best years of my life.” Of course, all the house staff started laughing. But it was really one of those years during which you worked hard and played hard. You did not have much time to play so when you played you played hard. I was living with a couple of female medical students who were best friends. We had a great house in Cambridge and there were parties there all the time. I left that year to go back to Washington because I thought that was where I wanted to live and went back there to do my residency. WCR: You went to Georgetown to do your first year residency and then your cardiology fellowship. You simply wanted to live in the Washington, DC, area. JMI: I really missed being in Washington and I missed my old friends. By that time, my Boston friends had scattered to do their internships. I started thinking where I wanted to go and what I wanted to do. I thought I really wanted to go back to Washington. Fred Stohlman, who was the Chief of Medicine

and good friends with Dudley Jackson, who was the Chief of Medicine at Georgetown, helped me go back. WCR: You had only 1 year of residency before you started your cardiology fellowship. How did you enjoy the Georgetown atmosphere? JMI: I thought it was great. At that time you spent about a third of your time at Georgetown, a third at Fairfax Hospital, and a third at the Washington Veterans Administration Hospital. It was a tremendous variety. Every setting was very different from the other. I loved being back in Washington. I lived in Glover Park and walked to work. It was a beautiful place to live. Before I went back to do a year of medical residency, I had already been accepted as a cardiology fellow. Georgetown had a great house staff at that time. It was an enriching place from a clinical standpoint. WCR: You had the 2 years of fellowship in cardiology. When did you start thinking that maybe you might like a career in academic medicine? JMI: The role model mentors at Georgetown were outstanding clinicians and teachers. I started to sense that their lives looked pretty interesting in terms of the teaching and what they were doing, plus it was about that time that I had kind of caught up educationally with what I had been exposed to at the Cleveland Clinic. I thought that was really exciting. Looking at what was happening— catheterization, angiography, bypass surgery—I now understood what was going on. I thought if I could somehow mix the practice of medicine with some of the other investigative possibilities that would be a lot of fun. WCR: How did you come to the National Institutes of Health? JMI: The chief resident when I was at Georgetown said to me, as I am sure he said to all the house staff, “Jeff, before you finish your residency you ought to write a paper.” I said, “Why?” He said there was something good about having gone through that experience. The article is going to be forever and you will always have something. I took an elective with Phil Schein and Jack MacDonald, both of whom had come from the National Cancer Institute of NIH to start the cancer center at Georgetown. They were dynamic people. It was the only elective available to me. They said I had 1 choice, oncology or nothing. I signed up and it turned out to be an unbelievable month. I know I personally influenced 4 other friends who were house staff at either Georgetown or George Washington to also take the same elective month. None of them had any previous ideas about going into oncology and they all became oncologists. One of them went on to become Head of the AIDS Program at NIH. We had a patient who had an ovarian carcinoma with spontaneous peritonitis. I reported the case with MacDonald and Schein. That elective and experience of having written that paper made an important impact on me. I developed a different view of oncology, but not enough to want to change from going into cardiology. WCR: How did you come to NIH?

80

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

JMI: About half way through my cardiology fellowship I decided I definitely wanted to go on to a career in academic cardiology. Rick Walsh, who was one of my fellow trainees, knew from the day he was born he wanted to be in academic medicine. We spent a lot of time talking about it. He was a great guy and is still one of my best friends. He became Head of Cardiology at the University of Cincinnati and just recently has taken over as Chief of Medicine at CaseWestern Reserve. Jules Gardin was another good friend in our fellowship class who also wanted to go into academic cardiology, and he is now Chief at the University of California at Irvine. We all talked and concluded that if we were going into academic medicine that we needed to go somewhere where we could learn to do investigative work to complement the clinical orientation we had had in our fellowship. At that time you were coming to Georgetown for weekly pathology conferences. You were obviously a very charismatic teacher and had the ability to make pathology relate to what I was doing in clinical medicine. We also spent a month during our cardiology fellowship at the Armed Forces Institute of Pathology with Chip McAllister. I had a great time with him and got to see a tremendous variety of pathology. We also had a month at the NIH. All the Georgetown fellows rotated out to NIH for a month. Those were the glory days of the Cardiology Branch of the National Heart Institute. I found that environment heaven. People got paid to spend all day asking questions and getting answers. They also took care of patients. I thought what could be better. At the time, since all the fellows knew you, it was easy to come to your lab while we were rotating at the NIH. It seemed to be the place I wanted to be. I could stay in Washington. At the same time I could go to an environment that was wonderful and, as I thought about it, I thought the pathology, at least the way you were doing it, was something I could relate to. I could see how I could use this as an opportunity in academic medicine. It also seemed to me that you learned a lot from the pathology about how to do things clinically. The way you did the clinicopathologic correlations made sense clinically so it just seemed like a natural. WCR: You were obviously quite productive during those 2 years. How did it work out that you came back to Tufts? JMI: I was looking at a couple of different jobs. Then one day I was in Steve Epstein’s office. We were talking and he happened to get a call from Dr. Sheldon Wolff, who had been at the NIH before he became Chief of Medicine at Tufts. Steve put his hand over the phone and said Shelly needs another cardiologist at Tufts and Steve asked me if I wanted to go there. I went the next week to meet Shelly. The hard part was that I did not want to leave Washington. At the same time, I knew that if I was going to do something on my own, having been trained by you to do cardiac pathology, it was almost imperative that I go away because I could not really do anything independently in Washington at that time. It seemed to me that this would be

a good thing to do at the time so that I could develop independence. WCR: You returned to Boston when? JMI: October 1979. WCR: You spread out in a lot of different areas. You did retain the pathology arena for a long time and you are still doing some of that but you got into the cath lab quickly. JMI: Part of the deal was the job I was looking at. (It seems naı¨ve in retrospect.) I was absolutely intent on being able to work both in the cath lab and do cardiac pathology. We now joke about the standard “cath/path package.” Of course, it was not standard at all. It did not exist. My thinking was that if you are working in a cath lab nobody is ever going to question that you are earning your living. Then you can take a little bit of a chance with the investigative part of what you want to do. With the jobs I was looking at I would only go there on the condition that I would have a joint appointment in pathology and I would spend roughly half my time doing cardiac pathology and the other half working in the cath lab from day 1. WCR: You started doing angioplasty quickly? JMI: At that point angioplasty had not yet been done in Boston! Shortly afterwards, however, Peter Block at the Massachusetts General Hospital and David Faxon at Boston University began performing coronary angioplasty. Just as I left the NIH I remember Sones telling me how he had just come back from a meeting with Grunzig and he was very excited about angioplasty. At that same time, Kenny Kent began doing it in Washington, DC. I remember a Thursday night conference at Georgetown at which Kenny Kent presented a patient of his who had angina 1 day and did not have it the next day. He opened the patient’s shirt and no scars were on his chest. He said what do you think happened to this patient? It was the first angioplasty that had been done in Washington. I started doing angioplasty the first or second year I was back at the New England Medical Center. Everybody was learning it by doing it at that time. WCR: How did you get into lasers? JMI: After leaving the NIH and just after getting to Boston, angioplasty exploded. I was thinking to myself, “You dunce, why are you so stupid? First of all, you had the advantage of Sones’ having gone over to meet with Grunzig in the earliest days of its development, and he tells you about it and you just pass it off and don’t give it a second thought. Then Kenny Kent did it in Washington. So you had a second chance to get involved and you blew it again. This is the biggest thing that has happened since Sones did the first angiogram and Favalaro did the first bypass operation and you really blew it. So if something else comes along that looks like it is going to be angioplasty you better make damn sure you don’t miss the boat this time.” I was at a heart meeting session on angioplasty at the American Heart Association and George Abela presented a paper on some very simple studies that he had just done at Gainesville, Florida, in which they had used a laser to show that they could ablate plaque in coronary arteries in vitro. I thought, “Okay this is INTERVIEW: JEFFREY MICHAEL ISNER

81

the next big thing coming along and I don’t want to just ride this one. I want to be a conductor.” It was obvious, however, that if you were going to do this you had to have a laser. I looked through the yellow pages in the telephone directory and tried to find out where I could get a laser. I could not find one anywhere. I figured if there were a laser in Boston that it would be at Massachusetts Institute of Technology. I called MIT and said I was a physician and wanted to meet someone who had a laser. They mentioned Fred Bowman. He did not have a laser but he said he would keep my name in mind if he found anyone who wanted to do something related to what I was talking about. Bowman was at a cocktail party and ran into Richard Clarke who was a Chemistry Professor at Boston University. Bowman called and told me about Richard Clarke who had a laser and worked on photosynthesis. Clarke was getting tired of doing that and was excited about what I was talking about and that I should give Clarke a call. I called Richard Clarke and he subsequently became one of my best friends. We hit if off right away. He is a great guy and one of the smartest people I have ever met. At the time I was single and he was single so we had almost unlimited time to work together. For me it was like going back to school again because I was learning about things I had never really paid much attention to before. It was a whole new vista and was the beginning of a great collaboration and a great personal friendship. WCR: Your bringing the laser along was really your initiation into investigative medicine. Isn’t that correct? JMI: Yes, that is right. WCR: How is this laser going to work out as far as its usefulness in producing holes in the myocardium? Are you optimistic about it? JMI: I am not terribly optimistic about it. The NIH convened a panel in about 1983 when many of us were just beginning to work with lasers and cardiovascular disease. The panel was convened to try and help the NIH decide whether they should make an investment in this technology. I was assigned the job of giving a talk about what was then called “the Mirhoseini procedure.” At that time, Mirhoseini was using a laser to create channels in the myocardium. Unfortunately, he was forced to do this in conjunction with bypass surgery. It was always impossible to decide whether it was the laser or bypass that was helping the patients. It was a procedure that everybody found intriguing. Many people were skeptical but nobody could dismiss it. It almost died on the vine and then subsequently it has had a rebirth. There have been a lot of interpretations about how this procedure works. Angiogenesis has been the latest interpretation of how this procedure works. I think it is hard to say. There have been so many things in interventional cardiology that defy logic. Even though balloon angioplasty was shown to be very effective, it took a long time to understand the mechanism of its effectiveness. Most interventionalists came to the conclusion early that they were not going to be concerned about how these things worked, but if they seemed useful, they could figure out the

mechanism later. As a result, there was a lot of empirical investigation. Enough effort is being applied to this right now that if it is effective we will know. WCR: Are you doing it now? JMI: No. We elected not to. WCR: Do you think it is going to work out from an intraarterial standpoint? Can you get enough holes in the myocardium intraarterially versus intraoperatively? JMI: I think so. I believe it still remains to be seen whether either the intraoperative or percutaneous approach will be definitive in terms of stand-alone therapy. WCR: Dr. Isner, you have become the leader in gene transfer angiogenesis. How did that come about? JMI: It was a combination of a couple of things. With lasers, we were very well funded by the NIH and had a very productive laboratory. We aimed at both applied research and basic research. When the lasers moved into the clinic, it became clear that it was going to be tough to continue to interest the NIH in funding fundamental laser-tissue interactions. That became painfully clear to me when we tried to renew a laser grant after having been very productive. It was around the time when cardiologists were starting to appreciate that there was something to be gained from molecular biology. WCR: This was what year? JMI: It was about 1989. WCR: You came to St. Elizabeth’s in 1988? JMI: Yes. I had a couple of talented fellows from Canada, Guy Leclerc and Jeff Pickering, who came here funded by the Canadian Heart Association. They came to work on laser-tissue interaction. They got here and I said “You know what. I have news for you. I am not sure it is in your best interest or mine to pursue lasers further. Molecular biology is here for cardiologists and I think it would be good for both you and me if we got involved. We are going to learn this together.” I was lucky enough that we had gotten one of our other laser grants renewed. I said, “We are going to use some of the support to bootstrap ourselves so that we can develop some expertise in molecular biology.” I recruited a fellow from Bob Adelstein’s lab at the NIH who helped us set up our laboratory. I sent Guy Leclerc off to Hubert Wolfe’s lab to learn how to do in situ hybridization. Together, we started developing some rudimentary expertise in molecular biology. At the same time, we lacked a focus. What do we do with this? At that time, directional atherectomy was beginning, and then we had access to plaques. Eric Topol was just starting the CAVEAT study. I was fortunate in that Eric subsequently became a very close friend and was able to arrange for us to be the core pathology laboratory for the CAVEAT study. By applying in situ hybridization and immunohistochemical techniques to these specimens from live patients, we figured we might learn a little more about the pathogenesis of atherosclerosis and, in particular, restenosis. Up to that time, studies of atherosclerosis and restenosis were limited to study of autopsied patients. All of a

82

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

sudden, we could get “live” specimens! We took advantage. Also, in 1989 Betsy Nabel published her article in Science describing the ability to do arterial gene transfer in live animals. This was it. This was the perfect way to marry interventional cardiology and molecular biology. It gave us the focus we needed. We quickly got Betsy out here to give grand rounds and she was exceptionally generous in talking with us and bringing us up to speed on this whole new concept of gene transfer; she subsequently became a good friend. We also had a very close association at that time with Boston Scientific in terms of developing catheters for local drug delivery. Thus, we could marry what abilities we had in the animal lab to what we had learned in molecular biology. It also seemed like a great way to study both the elements responsible for restenosis and at the same time maybe use gene therapy as a means of developing a new way to approach restenosis. The final piece was this. When we first had started using lasers in the clinic in the mid- to late 1980s, the initial investigations were in the peripheral arteries. At that time, we were doing these procedures at the New England Medical Center with the radiologists and the vascular surgeons with an absolute minimum amount of cooperation. As we started doing that work, we were forced to learn about peripheral vascular disease. WCR: When was that? JMI: 1986. When learning about the peripheral arteries and seeing how limited the therapeutic options were there, I developed an interest in this area. I saw a real opportunity to create an integrated program for the care of patients with peripheral vascular disease. One of the major reasons I came to St. Elizabeth’s was an opportunity to establish from ground zero a true multidisciplinary group to include radiologists, vascular surgeons, and cardiologists. I was able to bring Kenny Rosenfield with me at that time who was one of our cardiology fellows at the New England Medical Center. Kenny helped start our peripheral vascular program, which was the first program of its kind in Boston and one of the very few in the country. We started seeing lots of patients with very severe peripheral arterial disease and most had failed surgery and were poor candidates for angioplasty; indeed, that is the only reason they were sent to us, that is as a last resort before amputation. I remember as a Georgetown fellow Helen Taussig’s visit and her telling the story about how, as a woman coming out of Harvard Medical School, there had been very limited opportunities academically just because she was a woman. She was able to get a position on the faculty at The Johns Hopkins Hospital, but when she got there there was such prejudice that they told her, “Look, why don’t you go take care of the blue babies because there is nothing that can be done for them anyway. There is nothing to lose by having you do that.” I remember her saying how she was so angry about it that she said she was determined to find something that she could do for those “blue babies.” The rest is history. She got involved with Blalock and did find something that could be done for those babies.

When I saw the patients with critical limb ischemia, I thought that this was the adult equivalent of the “blue baby.” Everybody sends these cases because they say there is nothing else that can be done. When there is nothing left to be done, an opportunity arises to make a contribution! We had this large stable of patients with bad peripheral vascular disease. We were aware of Judah Folkman’s long-standing campaign to neutralize the growth and metastasis of malignant tumors by neutralizing growth factors responsible for the growth of blood vessels that supported these tumors. If we could do the opposite, that is, promote blood vessel growth in these patients’ legs, maybe it would be just enough to prevent amputation in them. About that time we were recruiting a new Chief of Cardiovascular Surgery here. I was at the beach at the Cape and ran into neighbors who talked about a friend of theirs in Montreal who is such a great guy and who wants to leave Canada. He was looking for a position in the USA and he is the greatest cardiovascular surgeon on the planet. (Of course, I figured this is the way my parents talked about me.) They said, “Would you mind if we have him get in touch with you?” I said, “Oh, yes sure.” So he called me and his name is Jim Symes. He wanted to see what was going on and he sent me his CV. All of a sudden I find out that my friends on the beach were right! This guy, at least on paper, was a very productive academic cardiovascular surgeon. He was both a vascular surgeon and a cardiac surgeon. He came down to visit and turned out to be even better in person than he was on paper. He is a tremendously wonderful person and, again, he became another one of my very close friends. We were able to recruit him. After he got here I learned that he had worked with Vineburg as one of his trainees, and that procedure had stimulated his interest in angiogenesis. I told him of our idea to use growth factors to promote collateral vessel growth in these terrible peripheral vascular disease patients. He replied: “That is funny. We just talked recently to a guy from Genentech who said they had a new growth factor.” We called up Genentech, and Napoleon Ferrara, who had identified vascular endothelial growth factor (VEGF), came shortly thereafter to Boston. We presented the idea to grow new blood vessels in the legs of these patients with terrible peripheral vascular disease. We could take advantage of some catheterbased techniques to introduce the protein. We also thought it might be possible to do this with gene therapy. We were starting to deal with a couple of different catheters in our lab. We already knew we could deliver a so-called reporter gene percutaneously via a couple of catheters we were working with. They gave us some material to try it out and Satoshi Takeshita immediately showed that the protein would work. However, we were unable to persuade Genetech to proceed with a clinical trial. We knew we could not make recombinant protein ourselves, but if gene therapy could be shown to work, we felt we could “manufacture” naked DNA in our own facility. We then decided to try doing that with gene therapy as well. An observation Douglas Losordo in our laboratory had INTERVIEW: JEFFREY MICHAEL ISNER

83

made was to show that if a gene encoded for a protein that was secreted rather than a protein that remained within the cell, even so-called naked DNA (without viral vectors) could actually yield significant evidence of gene expression. It turned out that VEGF was a secreted protein, one of the only angiogenic growth factors at that time that was known to be secreted. We took advantage of all this to develop a gene therapy approach in the lab to grow collateral blood vessels in these patients with critical limb ischemia. Now for the first time we saw the goal line. That is how it all crystallized. WCR: You have moved from intraarterial peripherally to intramuscular peripherally. How have intramuscular injections worked out? JMI: We were being sent a lot of peripheral vascular patients, and in some of them we could not get access to the arteries of the leg because the atherosclerotic plaque was too extensive. We decided we needed another option. We thought perhaps we could take advantage of the intramuscular injection approach. In the lab, Yukio Tsurumi had documented that the intramuscular delivery was just as effective as the intraarterial delivery, so we decided to apply that route to patients. We first used the intraarterial approach on December 7, 1994, Pearl Harbor Day! We were very concerned that that was a day that would live in infamy again. That was when the lab was really cresting. After years of trying to put things together, we were ready to do cardiovascular gene therapy for the first time in a patient. We were tremendously excited. We thought we had a really clever way to do it. When we did the first intramuscular injection because we did not have anything else to offer the patient, I remember walking out of the room and thinking to myself, “You just did something that is about as close to voodoo as you could possibly get.” The patient, a 37-year-old woman, had a huge ulcer in her lower leg, had been recommended to undergo below-knee amputation and she was on a “ton” of narcotic medicines for leg pain. They are looking to you as if you can provide some hope and you come in and do this kooky thing where you take a needle and do injections into the patient’s leg, not having any idea where to place the needles. WCR: How many did you do? JMI: We did 4 injections. WCR: In the upper thigh? JMI: I got together with our vascular surgeon, Dr. Sy Razvi, and asked where he thought we ought to inject? He suggested above the knee and below the knee, at sites where we could palpate muscle and where we knew we were not going to injure a nerve, or find ourselves in an artery. We did a couple above the knee and a couple below the knee where we could palpate some good muscle. The next week the patient came back and when asked how she was doing she said, “There is something happening. I don’t know what is going on but I can feel something happening.” We figured this was a placebo effect. Two weeks later she came back again and said, “You know, I am telling you there is really something going on here.”

At 3 weeks, she had a measurable increase in her ankle-brachial index, which we had had never seen in any patient who had intraarterial gene therapy. At 4 weeks, we did an angiogram and we saw new blood vessels. She had a marked improvement in her anklebrachial index, and by 4 to 5 weeks we started to see the ulcer filling in. The leg pain also was lessening. We did a second round of injections and by about 4 weeks later her ankle-brachial index had gone from 0.3 to 0.6. (The published criteria for successful angioplasty or bypass surgery sequence is an increase in the ankle-brachial index of only 0.1.) This lady had increased from 0.3 to 0.6! One of our plastic surgeons, Dr. George Volpe, agreed that if the progress continued after her 8-week follow-up that she would be a candidate for a split-thickness skin graft. He went ahead and did that and low and behold the graft took. He said in the operating room, “You know this thing is bleeding like a stuck pig. You can leave. There is no question. Go home. I can tell you this graft is going to take.” We still could not believe it but the graft started to heal perfectly. Sixteen weeks after the intramuscular injections, she had been successfully weaned from methadone, duragesic, percoset, and Elavil, all of which she had been taking for this pain. She went from being wheelchair bound to being completely ambulatory. She went back to work as a grade school science teacher by the next fall. By that time, we had tried the intramuscular injections in a couple of other patients and we were seeing a quantum leap in the improvement that the patients were experiencing. From that point on we did not do any more intraarterial gene therapy. WCR: That started what year? JMI: We started the intramuscular injections in 1996. WCR: How many injections do you do now? JMI: Currently, we are doing 8 injections at each setting. We do 2 or 3 treatment sessions. WCR: Are the injections painful at all? JMI: Not much. Most patients don’t experience any significant discomfort. Rarely, a patient will take 2 tablets of Tylenol afterwards. For the most part, it is like getting your flu shots. WCR: You send them home quickly after that? JMI: Yes. We now do the injections as an outpatient procedure. They go home immediately afterwards. WCR: Who is paying for this? JMI: That is a good question. The insurance companies don’t pay for it. We have done this thus far without industrial support so the hospital has absorbed a lot of the costs of this therapy. Dr. Michael Collins, our President and Chief Executive Officer, has been tremendously supportive. WCR: At first I gather you had a problem getting patients with peripheral vascular disease. Since your procedure has been so publicized and has been successful I gather getting patients is not a problem now? JMI: Getting patients is absolutely not a problem, although most patients we see are self-referred. Some are referred by cardiologists and internists. There is increasing public awareness of this procedure now.

84

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

WCR: I gather that you have had few referrals from vascular surgeons? JMI: Very few are sent to us by vascular surgeons. WCR: What is the latest interval that you record an angiogram after the injections to see whether these new channels continue to stay open? JMI: We do no further angiograms after 1 year; our clinical follow-up is now out to 2 years. WCR: They are still looking good at that point? Now you are moving to the heart. What is happening there? JMI: Yes. We have adopted the approach for the heart that we used in the legs. Although early on we always thought we would do it by the intraarterial approach, we use the intramuscular route, whereby 100% of the DNA we are giving gets into the muscle. Not all of it gets into the cells but at least 100% of it is in the target tissue. We elected to take that approach for the heart and take advantage of the minimally invasive thoracotomy type of approach to deliver the gene that way. Jim Symes now has treated 14 patients. We began this in February 1998. Surprisingly, despite the fact that we started with a very low dose of the naked plasmid DNA, we have again seen some dramatic results. In fact, our early experience suggests that this may work better in the heart than it does in the leg, just as angioplasty surgery, or drugs typically do. WCR: Which cardiac patients are you now doing this procedure on? JMI: Currently, we are doing it in patients who are not candidates for any conventional treatment, including medical therapy, surgery, or angioplasty. WCR: This is the end of the line for them just like your peripheral vascular patients. Are you are optimistic about the heart? JMI: We have demonstrated both subjectively and objectively that it works in the heart. It is a matter of how broadly can you extend this therapy to the whole universe of patients with ischemic heart disease. WCR: You were the first to do this in the legs and the first to do it in the heart? JMI: It was by no means an individual effort. Ann Pieczek, Orit Manor, Marianne Kearney, Iris Baumgartner, Peter Vale, Guenter Rauh, Doug Losordo, and Jim Symes all made critical conditions. Work by Takayuki Asahara in our laboratory also led to the first clinical trial of gene therapy to prevent restenosis. WCR: Your office quarters, clinic and laboratory space is quite impressive. How big an operation do you have now? How many people do you have in your vascular medicine division here at St. Elizabeth’s? JMI: Along with Kenny, Bob Schainfeld, and myself, we have 6 nurses, several technicians, several secretaries, and 3 fellows. It probably totals, together with our research group, about 45 people. That is 43 more than when I came! WCR: When you came here in 1988 there were 2 of you. Not only have you increased it multifold but the hospital has built you a wonderful setup. JMI: They have been very generous. It has been very important for us to have an area where we could

bring all of our personnel together. Previously, we were scattered all over the hospital. We are now more efficient. The hospital was also very generous in giving us a superb physical plant for our research division, and the resources to recruit accomplished scientists like Ken Walsh, Vicente Andres, and Takayuki Asahara. The people in our research division work intimately with our clinical group, both in vascular medicine and in cardiology. WCR: You have taken your bench research directly to the patient. Your bench research was with an absolute goal line in mind from the beginning. You have acquired a tremendous amount of money from NIH and other sources to support all of these endeavors. How much grant money have you garnered since 1979? JMI: About $20 million. WCR: Each one of these protocols you fill out to get a grant looks like a book. It is a good thing you had to have all those sports-article deadlines. JMI: Never were any of those sports articles as oppressive to author as any of these grants. WCR: You have always been busy. You have never worked just 1 job or 1 task or 1 activity in your life. What is your life like now? What time do you get up in the morning? What time do you get to the hospital? What time do you leave the hospital? What time do you get home? What time do you go to bed? Can you describe a typical day? JMI: I usually get up about 4:45 A.M., which conveniently is the same time my wife gets up because she is a superb swimmer and swims 2 miles every morning before she gets the kids off to school. I usually try to work for a couple of hours at home. I try to do my writing in the mornings. I remember as a kid reading something from an article about Michael De Bakey where he said that early morning was always the most productive time of the day for him and it always stuck in my mind. When I get up early in the morning that is definitely the best time for me to write. I usually get to the hospital by about 8:00 A.M. Early on in my career when I was single, it was endless. I would stay here until I was done, which could mean eating at the hospital and staying late. Once I got married and had children, I always made it a priority to be home for dinner unless there were some unusual circumstances. I usually get home about 6:30 P.M., have dinner, spend some time with the kids, and work from about 9:00 to 11:30. I usually go to bed at 11:30 to midnight. WCR: What about on weekends? JMI: I typically have managed to get up and do some writing early on Saturday and Sunday mornings before everybody is up, and then have the rest of the day free for my family. On Sunday night I do some more work. Linda and I have had an agreement that I would do whatever traveling was required during the week. Weekends were a time we were all going to spend together, and for the most part I have tried to adhere to that. That post-dinner time and weekends are times committed to family. WCR: When did you get married, Jeff? INTERVIEW: JEFFREY MICHAEL ISNER

85

JMI: I got married 13 years ago when I was 37. WCR: Jack Kennedy got married when he was 36

so you were 1 year after him. Your 3 children are how old now? JMI: Josh, Jessie, and Mathew are 12, 11, and 5. WCR: What are your goals, desires, or ambitions now? You are 50 years old and you have been going at it steadily, strongly, and competitively for a long time. What if somebody offers you the Chairmanship of Medicine or Chief Executive Officer of a developing company. How would you handle that? JMI: I said I would never go into academic medicine and that is where I have spent my life so I would never say never about anything. To me the thing that really motivated me more than anything else is a sense that I don’t want to feel that I was just kind of passing through during this lifetime. I do not want to just be one more person that came and left. I always wanted to do something that could make a little difference. Certainly in medicine, after being exposed to Sones at the Cleveland Clinic and the things he had done, I thought if I ever had the opportunity to be able to do anything that could really change the way medicine is practiced, that is what I would like to do. It is still the way I feel. You need a certain amount of resources to be able to achieve things. For any opportunity to be attractive, it would have to provide a quantum leap in what I thought I could achieve. WCR: It is very exciting that you took an area of basic science and molded that into a therapy which was the only hope of these patients, and you started this endeavor only 10 years ago. When is this going to spread outside St. Elizabeth’s Hospital? JMI: There are already other groups that are working in this area. We are nearing the end of the Phase I single center trial. My hope is that before the end of this year we will be into a Phase II multicenter trial that will involve other centers and hopefully with a catheter-based technique for doing the heart. I think the peripheral application is right now about as simplified as it can possibly get. I also hope the peripheral vascular work will soon be expanded to a multicenter basis. WCR: You hope to move away from the desperate person, particularly with peripheral vascular disease, to treat patients with less severe leg ischemia? JMI: That is the next logical place to go with this. WCR: Do you envision the application of this therapy to the myocardium as care for acute myocardial ischemia, such as unstable angina? It takes how long for the vessels to generate? JMI: That is really a great question. We have done a study in animals where we have treated acute limb ischemia. It worked in the animal model fairly effectively. Whether that could be used in the case of acutely ischemic myocardium is unknown. The gene expression takes probably 18 to 24 hours to begin. Although they develop quickly, the vessels still require days, maybe up to 14, to develop. As acute treatment, I would be more optimistic about the therapy applied to unstable angina than acute infarction.

WCR: Chronically, from the heart’s stand point, which patients do you envision this therapy to be used for? JMI: It certainly is going to be useful for patients who do not have any other therapeutic options. We can say that with confidence. Everything else is speculation. I don’t think it is completely unrealistic that we might soon be in a situation where this might be a simple enough thing to do, that you could do a diagnostic catheterization on a patient, and, perhaps because they are not an ideal angioplasty or bypass candidate, you might go ahead and do an intramyocardial injection of the gene. If the patient is not unstable we can afford to watch the patient for a couple of weeks, and if they get better, angioplasty or bypass might be avoided. If it seems to be as benign as it appears to be from the earlier experiences, earlier application of gene therapy might be reasonable rather than using it as last-line therapy. It might be possible to set the clock back by 5 or 10 years. You may be buying the patient some important time, i.e., delay angioplasty or bypass and consequently the complications of each of these procedures. WCR: You would envision that it be given via catheter in the left ventricle? JMI: Right now that is the way I would envision it. It is something we know we can do because Peter Vale and Doug Losordo have already done it in our laboratory in non-human animals. We might be able to find some alternative approaches. WCR: Right now you have time for your work and your family and that is about it. You don’t have any burning hobbies or do you? JMI: One good thing that came from my first 2 years of medical school in Boston was learning to sail—I did a lot of that before getting married. Subsequently, I have spent more time with hobbies the rest of the family enjoys more. We do a lot of skiing together. We play a lot of golf together. Other than socializing with friends that is probably the way we spend our time. WCR: So you try to keep the weekend to being a husband and a father like your parents? JMI: Yes. That was the model that my parents made for me. I think it was the model of Linda’s parents. Our family is very important to both of us. WCR: Where is Linda from? JMI: She is from a wonderful family of 8 in Braintree, a suberb of Boston. WCR: Jeff, is there anything you would like to discuss that we haven’t? JMI: When you were talking about people that have had an impact on me you did not give me the opportunity to discuss you. I thought I had an outstanding work ethic when I came to work for you. I remember the first weekend I was coming to work for you, having just finished my cardiology fellowship. It was the July 4th weekend. I remember coming to your office. I was with some friends and we had a place at Ocean City we were going to. I thought I would just drop by to say hello. I said, “I just wanted to say ‘hi.’ I am on my way to the beach.” You had this kind of

86

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82

stunned look on your face. You came out with this big box of files of 150 patients who had died of rupture of the heart and said, “Maybe you can take these with you over the weekend and take a look at them.” I remember walking out to the car and this girl I was with said, “What is that?” I said, “I got a little homework.” We drove off to Ocean City with this box full of charts. I think you really turned it up a notch for me in terms of what was required to really achieve something and write well and think creatively. You used to make us look at all these cases and write down at the bottom of their file what is new about this case? That seemed like a pretty obvious thing but a lot of people don’t look at it that way and as a result of that if I ever looked at a patient subsequently or if I ever looked at a research opportunity I started always looking at it that way. A lot of people who did not come from the experience I had in your lab never ever understood what it took to get something to the goal line. That was really an invaluable lesson. WCR: You are very generous in your comments, but you did not learn anything about what you are doing now from me. JMI: That may be true but I am not sure that without the experience I had in your lab I would be doing any of the things I am doing now. WCR: Jeff, I appreciate those generous comments. I appreciate your time. I am sure the readers of The American Journal of Cardiology will be enormously intrigued. Thank you. JMI: Thank you for the opportunity, Bill. JMI’s BEST PUBLICATIONS AS SELECTED BY HIM 6. Isner JM, Roberts WC. Right ventricular infarction complicating left ventricular infarction secondary to coronary heart disease. Frequency, location, associated findings, and significance from analysis of 236 necropsy patients with acute or healed myocardial infarction. Am J Cardiol 1978;42:885– 894. 15. Isner JM, Sours HE, Paris AL, Ferrans FJ, Roberts WC. Sudden unexpected death in avid dieters using liquid-protein modified fast diet: observations in 17 patients and the role of the prolonged Q-T interval. Circulation 1979;60:1401– 1412. 22. Isner JM, Kishel J, Kent KM, Ronan JA Jr, Ross AM, Roberts WC. Accuracy of angiographic determination of left main coronary arterial narrowing: angiographic-histologic correlative analysis in 28 patients. Circulation 1981;63:1056 – 1064. 36. Isner JM, Carter BL, Bankoff MS, Konstam MA, Salem DN. Computed tomography in the diagnosis of pericardial heart disease. Ann Intern Med 1982; 97:473– 479. 74. Deckelbaum LI, Isner JM, Donaldson RF, Clarke RH, Laliberte S, Aharon AS, Bernstein JS. Reduction of pathologic tissue injury using pulsed energy delivery. Am J Cardiol 1985;56:662– 667. 77. Isner JM, Donaldson RF, Deckelbaum LI, Clarke RH, Laliberte SM, Ucci AA, Salem DN, Konstam MA. The excimer laser: gross, light microscopic, and ultrastructural analysis of potential advantages for use in laser therapy of cardiovascular disease. J Am Coll Cardiol 1985;6:1102–1109. 94. Isner JM, Estes NAM, Thompson PD, Nordin MR, Subramanian R, Miller G, Katsas G, Sweeney K, Sturner WQ. Acute cardiac events temporally related to cocaine abuse. N Engl J Med 1986;315:1438 –1443. 95. Clarke RH, Isner JM, Donaldson RF, Jones G. Gas chromatographic-light microscopic correlative analysis of excimer laser photoablation of cardiovascular tissues. Evidence for a thermal mechanism. Circ Res 1987;60:429 – 439. 113. Steg PG, Gal D, Rongione AJ, DeJesus ST, Clarke RH, Isner JM. Effect of argon laser irradiation on rabbit aortic smooth muscle: evidence for endotheliumindependent contraction and relaxation. Cardiovasc Res 1988;22:747–753. 115. Isner JM, Gal D, Steg PG, DeJesus ST, Rongione AJ, Halaburka KR, Slovenkai GA, Clarke RH. Percutaneous in vivo excimer laser angioplasty. Lasers Surg Med 1988;8:223–232. 117. Isner JM, DeJesus ST, Clarke RH, Gal D, Rongione AJ, Donaldson RF. Mechanism of laser ablation in an absorbing fluid field. Lasers Surg Med 1988;8:543–554. 120. Isner JM, Samuels DA, Slovenkai GA, Halaburka KR, Hougen TJ, Desnoy-

ers MR, Fields CD, Salem DN. Mechanism of aortic balloon valvuloplasty. Ann Intern Med 1988;108:377–379. 139. Steg PG, Rongione AJ, Gal D, DeJesus ST, Clarke RH, Isner JM. Pulsed ultraviolet laser irradiation produces endothelium-independent relaxation vascular smooth muscle. Circulation 1989;80:189 –197. 140. Chokshi SK, Moore R, Pandian N, Isner JM. Reversible cardiomyopathy associated with cocaine intoxication. Ann Intern Med 1989;111:1039 –1040. 153. Isner JM, Rosenfield K, Kelly S, Losordo DW, DeJesus ST, Palefsky P, Langevin RE, Razvi S, Pastore JO, Kosowsky BD. Percutaneous intravascular ultrasound examination as an adjunct to catheter-based interventions: preliminary experience in patients with peripheral vascular disease. Radiology 1990;175:61– 70. 163. Isner JM, Rosenfield K, Losordo DW, Rose L, Langevin RE Jr, Razvi S, Kosowsky BD. Combination balloon-ultrasound imaging catheter for percutaneous transluminal angioplasty: validation of imaging, analysis of recoil, and identification of plaque fracture. Circulation 1991;84:739 –754. 164. Rosenfield K, Losordo DW, Ramaswamy K, Pastore JO, Langevin RE Jr, Razvi S, Kosowsky BD, Isner JM. Three-dimensional reconstruction of human coronary and peripheral arteries from images recorded during two-dimensional reconstruction of human coronary and peripheral arteries from images recorded during two-dimensional intravascular ultrasound examination. Circulation 1991; 84:1938 –1956. 173. Pickering JG, Weir L, Rosenfield K, Stetz J, Isner JM. Smooth muscle cell outgrowth from human atherosclerotic plaque: implications for the assessment of lesion biology. J Am Coll Cardiol 1992;20:1430 –1439. 174. Mosseri M, Varticovski L, Fingert F, Chokshi S, Isner JM. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res 1993;53:3028 –3033. 175. Gal D, Chokshi SK, Mosseri M, Clarke RH, Isner JM. Percutaneous delivery of low-level laser energy reverses histamine-induced spasm in atherosclerotic yucatan microswine. Circulation 1992;86:756 –768. 176. Dietz WA, Tobis JA, Isner JM. Failure of angiography to accurately depict the extent of coronary arterial narrowing in three fatal cases of percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1992;19:1261–1270. 177. Leclerc G, Gal D, Nikol S, Kearney M, Weir L, Isner JM. Percutaneous arterial gene transfer in a rabbit model efficiency in normal and balloon-dilated atherosclerotic arteries. J Clin Invest 1992;90:936 –944. 179. Losordo DW, Rosenfield K, Pieczek A, Baker K, Harding M, Isner JM. How does angioplasty work? Serial in vivo morphometric analysis of mechanisms of angioplasty in humans using intravascular ultrasound. Circulation 1992;86:1845– 1858. 191. Pickering JG, Bacha PA, Weir L, Jekanowski J, Nichols JC, Isner JM. Prevention of smooth muscle cell outgrowth from human atherosclerotic plaque by a recombinant cytotoxin specific for the epidermal growth factor receptor. J Clin Invest 1993;91:724 –729. 192. Losordo DW, Leclerc G, Gal D, Weir L, Takeshita S, Isner JM. Use of the rabbit ear artery to serially assess foreign protein secretion after site-specified arterial gene transfer in vivo: evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression. Circulation 1994;89:785–792. 198. Gal D, Weir L, Leclerc G, Pickering JG, Hogan J, Isner JM. Direct myocardial transfection in two animal models: evaluation of parameters affecting gene expression and percutaneous gene delivery. Lab Invest 1993;68:18 –25. 200. Isner JM, Rosenfield KR. Redefining the treatment of peripheral artery disease. Role of percutaneous revascularization. Circulation 1993;88:1534 –1557. 205. Pickering JG, Weir L, Jekanowski J, Kearney M, Isner JM. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization. J Clin Invest 1993;91:1469 –1480. 214. Takeshita S, Gal D, Leclerc G, Pickering JG, Riessen R, Weir L, Isner JM. Increased gene expression after liposome-mediated arterial gene transfer associated with intimal smooth muscle cell proliferation following vascular injury. J Clin Invest 1994;93:652– 661. 217. Riessen R, Rahimizadeh H, Blessing E, Takeshita S, Barry JJ, Isner JM. Arterial gene transfer using pure DNA applied directly to hydrogel-coated angioplasty balloon. Hum Gene Ther 1993;4:749 –758. 223. Takeshita S, Tsurumi Y, Couffinhal T, Asahara T, Bauters C, Symes JF, Ferrara N, Isner JM. Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. Lab Invest 1996;75:487–502. 224. Takeshita S, Zheng LP, Brogi E, Kearney M, Asahara T, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis: a single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hindlimb model. J Clin Invest 1994;93:662– 670. 225. Riessen R, Isner JM, Blessing E, Loushin C, Nikol S, Wight TN. Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries. Am J Pathol 1994;144:962–974. 234. Losordo DW, Rosenfield K, Kaufman J, Pieczek A, Isner JM. Focal compensatory enlargement of human arteries in response to progressive atherosclerosis: in vivo documentation using intravascular ultrasound. Circulation 1994;89:2570 –2577. 238. Bauters C, Asahara T, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM. Physiologic assessment of augmented vascularity induced by VEGF

INTERVIEW: JEFFREY MICHAEL ISNER

87

in ischemic rabbit hindlimb. Am J Physiol 267 Heart Circ Physiol 1994;36: H1263–H1271. 239. Brogi E, Wu T, Namiki S, Isner JM. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, while hypoxia upregulates VEGF expression only. Circulation 1994;90:649 – 652. 241. Isner JM. Vascular remodeling: honey, I think I shrunk the artery. Circulation 1994;89:2937–2941. 247. Bauters C, Asahara T, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM. Recovery of disturbed endothelium-dependent flow in the collateral-perfused rabbit ischemic hindlimb after administration of vascular endothelial growth factor. Circulation 1995;91:2802–2809. 248. Feldman LJ, Steg PG, Zheng LP, Chen D, Kearney M, McGarr SE, Barry JJ, Dedieu J-F, Perricaudet M, Isner JM. Low-efficiency of percutaneous adenovirus-mediated arterial gene transfer in the atherosclerotic rabbit. J Clin Invest 1995;95:2662–2671. 249. Takeshita S, Rossow ST, Kearney M, Zheng LP, Bauters C, Bunting S, Ferrara N, Symes JF, Isner JM. Time course of increased cellular proliferation in collateral arteries following administration of vascular endothelial growth factor in a rabbit mode of lower limb vascular insufficiency. Am J Pathol 1995;147: 1649 –1660. 251. Asahara T, Bauters C, Pastore CJ, Kearney M, Rossow S, Bunting S, Ferrara N, Symes JF, Isner JM. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in ballooninjured rat carotid artery. Circulation 1995;91:2793–2801. 256. Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM. Identification of 92 kD gelatinase in human coronary atherosclerotic lesions: association of active enzyme synthesis with unstable angina. Circulation 1995;91:2125–2131. 265. Isner JM, Kearney, Bortman S, Passeri J. Apoptosis in human atherosclerosis and restenosis. Circulation 1995;91:2703–2711. 269. Asahara T, Chen D, Kearney M, Rossow S, Passeri J, Symes JF, Isner JM. Accelerated restitution of endothelial integrity in endothelium-dependent function after phVEGF165 gene transfer. Circulation 1996;94:3291–3302. 273. Namiki A, Brogi E, Kearney M, Wu T, Couffinhal T, Varticovski L, Isner JM. Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chemistry 1995;270:31189 –31195. 274. Brogi E, Schatteman G, Wu T, Kim EA, Varticovski L, Keyt B, Isner JM. Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest 1996;97:469 – 476. 276. Isner JM, Pieczek RN, Schainfeld R, Blair R, Haley L, Asahara T, Rosenfield K, Razvi S, Walsh K, Symes JF. Early report: clinical evidence of angiogenesis after arterial gene transfer of ph VEGF165 in patient with ischemic limb. Lancet 1996;348:370 –374. 281. van der Zee R, Zollman F, Passeri J, Lekutat C, Silver M, Isner JM. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) augments nitric oxide release from quiescent rabbit and human vascular endothelium. Circulation 1997;95:1030 –1037. 286. Isner JM, Walsh K, Symes JF, Pieczek A, Takeshita S, Lowry J, Rosenfield K, Weir L, Brogi E, Jurayj D. Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease. Hum Gene Ther 1996;7:959 –988. 287. Isner JM, Walsh K, Rosenfield K, Schainfeld R, Asahara T, Hogan K, Pieczek A. Arterial gene therapy for restenosis. Hum Gene Ther 1996;7:989 – 1011. 289. Tsurumi Y, Takeshita S, Chen D, Kearney M, Rossow ST, Passeri J, Horowitz JR, Symes JF. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation 1996;94:3281–3290. 292. Van Belle E, Tio FO, Couffinhal T, Maillard L, Passeri J, Isner JM. Stent endothelialization time course, impact of local catheter delivery, feasibility of

recombinant protein administration, and response to cytokine expedition. Circulation 1997;95:438 – 448. 293. Van Belle E, Tio FO, Chen D, Maillard L, Chen D, Kearney M, Isner JM. Passivation of metallic stents following arterial gene transfer of ph VEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol 1997;29: 1371–1379. 296. Couffinhal T, Kearney M, Witzenbichler B, Losordo DW, Symes JF, Isner JM. Vascular endothelial growth factor/vascular permeability factor (VEGF/ VPF) in normal and atherosclerotic human arteries. Am J Pathol 1997;150:1673– 1685. 297. Kearney M, Pieczek A, Haley L, Losordo DW, Andres V, Schainfeld R, Rosenfield K, Isner JM. Histopathology of in-stent restenosis. Circulation 1997; 95:1998 –2002. 303. Van Belle E, Chen D, Silver M, Bunting S, Ferrara N, Symes JF, Bauters C, Isner JM. Hypercholesterolemia attenuates angiogenesis, but does not preclude augmentation by angiogenic cytokines. Circulation 1997;96:2667–2674. 305. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Schatteman G, Isner JM. Isolation of putative endothelial progenitor cells for angiogenesis. Science 1997;275:964 –967. 306. Tsurumi Y, Murohara T, Krasinski K, Chen D, Witzenbichler B, Kearney M, Couffinhal T, Isner JM. Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nature Med 1997;3:879 – 886. 309. Murohara T, Horowitz JR, Silver M, Tsurumi Y, Sullivan A, Isner JM. Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via receptor tyrosine kinase Flk-1 mediated production of nitric oxide and prostacyclin. Circulation 1998;97:99 –107. 313. Baumgartner I, Pieczek A, Manor O, Blair R, Walsh K, Isner JM. Constitutive expression of ph VEGF165 following intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998;97:1114 –1123. 324. Witzenbichler B, Asahara T, Murohara T, Silver M, Spyridopoulos I, Magner M, Principe N, Kearney M, Hu J-S, Isner JM. Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am J Pathol 1998;153:381–394. 325. Asahara T, Chen D, Takahashi T, Fujikawa K, Kearney M, Magner M, Yancopoulos GD, Isner JM. The Tie2 receptor ligands, angioprotein-1 and angiopoietin-2 modulate VEGF-induced postnatal neovascularization. Circ Res 1998;83:233–240. 326. Witzenbichler B, Maisonpierre PC, Yancopoulos G, Isner JM. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Bio Chem 1998;273:18514 –18521. 328. Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, Kearney M, Chen D, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest 1998;101:2567–2578. 329. Shyu K-G, Manor O, Magner M, Yancopoulos GD, Isner JM. Direct intramuscular injection of plasmid DNA encoding angiopoietin-1, but not angiopoietin-2, augments revascularization in the rabbit ischemic hindlimb. Circulation; in press. 330. Rivard A, Fabre J-E, Silver M, Chen D, Murohara T, Kearney M, Magner M, Isner JM. Age-dependent impairment of angiogenesis. Circulation; in press. 332. Couffinhal T, Silver M, Zheng LP, Kearney M, Witzenbichler B, Isner JM. Mouse model of angiogenesis. Am J Pathol 1998;152:1667–1679. 334. Isner JM, Baumgartner I, Rauh G, Schainfeld R, Blair R, Manor O, Razvi S, Symes JF. Treatment of thromboangitis obliterans (Buerger’s Disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg; in press.

88

JANUARY 1, 1999

THE AMERICAN JOURNAL OF CARDIOLOGYT

VOL. 82