Conversations with giants in medicine A conversation with Eugene Braunwald

Eugene Braunwald (Figure 1) is often carried out in probably 4,000 hospitals in give them relief from severe angina. We were called the father of modern , as the US. But, at that time there were only 12 in discussion with developing a large phase he was the first to define the pathophysiol- cardiac cath labs in the country. It was an 3 trial to get this device approved for mar- ogy of hypertrophic cardiomyopathy and eye-opening experience, to be in a serious keting, but coronary artery bypass graft sur- to demonstrate the salvage of ischemic research laboratory, and I became interested gery came on the scene and was superior to myocardium following coronary occlusion. in the pathophysiology of . carotid sinus nerve stimulation in relieving The full interview, with many more stories Later, I had a postdoctoral fellowship angina. But, all was not lost because it led about performing in the opera and his sem- with [Nobel Laureate] André Cournand, to my second, and more important, “aha” inal research discoveries, can be seen on the who also worked in , moment in the spring of 1968. We told our JCI website, http://www.jci.org/kiosk/cgm. but in the Columbia University division. I patients that if they had unusually severe JCI: Can you tell us about your path to spent a year there and that firmed my inter- pain, not the usual angina, they shouldn’t medical school? est in research, and also led to my being turn their carotid sinus stimulators on Braunwald: I was born in Vienna, , accepted by what was then the National because, if they were having an infarction, and had an idyllic childhood there with Heart Institute. That discharged my mili- we didn’t want their blood pressure to drop. an excellent school, and tutors in English tary obligation, as there was a doctor draft One of our patients, who had a stimulator, and piano. On March 12, 1938, everything during, and after, the Korean War. came into the Clinical Center with severe changed because Austria was annexed by The NIH years, which were from 1955 to chest pain and the ECG findings of an ongo- Germany. The Nazis came in, and the fury 1968, provided such a rich environment in ing . He did not listen against the Jews played out in a matter of terms of ideas, and the fact that there were to my advice and he kept the stimulator on. days. It was a very troubling period. We incredible colleagues and tremendous oppor- That evening, when I looked at the ECGs escaped from Austria at the end of July 1938 tunities for interaction with outstanding recorded while he had his myocardial infarc- with a couple of close calls. It was like The scientists in all areas of biomedical science. tion, I found that it varied in an interesting Sound of Music — except that there was no My assignment for the first two years was in way. When the stimulator was turned on, music. We ended up in London two days the Laboratory of Cardiovascular Physiol- the ST segments — the part of the ECG that later, literally with just the shirts on our ogy with Stanley Sarnoff, who was a brilliant reflects ischemia — were almost normal. back. When war was declared in September physiologist who introduced me to a whole When I came along and turned the stimula- 1939, my brother and I were evacuated to new way of thinking about the circulation. tor off, it became more abnormal. This hap- a small village in Northern England. After We began to determine how much energy pened several times over the course of two living with a wonderful family for a couple the heart needs to do its work. We learned a hours. So, he was right and I was wrong. This of months, I got a postcard that our family lot over the course of 13 years about oxygen meant that even several hours into a myocar- was going to America. We took the President consumption and ischemia — how ischemia dial infarction you could still manipulate the Harding, which was one of the last passen- causes angina and how ischemia can cause a severity of ischemia. The traditional think- ger ships to cross the Atlantic because the full-blown myocardial infarction. ing had been that myocardial infarction was German U-boats were out in force. JCI: What lead you to your major dis- a sudden event. It was thought that a clot in We landed in New York and, after complet- coveries? the coronary artery that killed heart muscle ing grammar school, I landed at Brooklyn Braunwald: I’ve had basically two “aha” was like turning a light switch off. What Technical High School. I wanted to be an moments which came close together, the the experience with this patient suggested engineer, a field that reigned supreme dur- first in 1967 and the other in 1968. In 1967, was that maybe myocardial infarction was ing WWII. But, then I thought it was too I met Seymour Schwartz, a surgeon at the more like turning light down with a dim- impersonal and chose medicine. Engineering , and he showed mer, and that you could save heart muscle in concepts came in handy when, in medical me a colony of dogs in which he had pro- the course of a heart attack. Our subsequent school, I developed an interest in cardiology duced experimental hypertension. He had dog studies found that it was possible to do because cardiologists were either “electri- implanted an electrical stimulator on the that, and we began to publish on techniques cians” or “plumbers” — i.e., used concepts carotid sinus nerves, and this was effective in for protection of the ischemic myocardium from electrical or mechanical engineering. reducing the elevated blood pressure. Carot- and the reduction of infarct size. Those dog JCI: You took an elective in your last year id sinus stimulation also slows the heart experiments showing that infarct size could of medical school that introduced you to rate and reduces myocardial contractil- be reduced really put me on a different path, cardiology. ity. What occurred to me, on my way home and this led to our attempts to apply the Braunwald: When I entered my senior year from Rochester, was that carotid sinus nerve same principles to patients, which has been at NYU Medical School in 1951, research stimulation might be an effective way of a major subject of my subsequent research. electives were not a standard part of medi- reducing myocardial oxygen consumption, JCI: How did you come upon the discov- cal education in the US. However, I was able and might therefore be a great way of treat- ery and description of hypertrophic cardio­ to take an elective with Ludwig Eichna, who ing intractable angina. From the conception myopathy? directed a cardiac catheterization labora- of the idea to the first patient treated took Braunwald: That was an extraordinary tory at Bellevue Hospital. Cardiac catheter- six weeks. Patients would turn the carotid experience. In 1958, we studied a young man ization is now a diagnostic technique that’s sinus nerve stimulator on and this would at the NIH who had a loud heart murmur

The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 1 January 2013 1 conversations with giants in medicine

I don’t like steak three meals a day, seven days a week.” And, I began to feel a little bit about research that way. I became inter- ested in medical curriculum development, and what better way is there to do that than at a new medical school? JCI: You then moved on to be Chairman of Medicine within the Harvard system for 24 years. Braunwald: I had four very good years in La Jolla. But the problem was that the new gov- ernor of California, Ronald Reagan, made a decision not to build the school’s university hospital. I felt that we could not develop a great medical school without a great hos- pital. So, when the opportunity in Boston came along, I took that. My period in Cali- fornia prepared me for a much tougher job, and that was at the Brigham, which required a lot of reorganization and an emphasis on graduate medical education. Figure 1 JCI: In addition to the over 1,000 research Ushma Neill interviews Eugene Braunwald on October 23, 2012, in New York City. Image credit: articles you’ve written, you served as editor Semyon Maltsev. of Harrison’s Principles of Internal Medicine for twelve editions and you’re now on to the ninth edition of Braunwald’s Heart Disease, and shortness of breath with a large pres- pressure gradient. We puzzled about that, the definitive textbook of cardiology. sure gradient between the body of his left day in and day out, for a couple of months, Braunwald: I think that textbooks are ventricle and the aortic valve. We assumed when a second patient presented with iden- important in terms of education. One of the that he had a congenital subaortic stenosis, tical findings. We didn’t know exactly what things that gives me the most satisfaction is a pretty uncommon congenital condition, was going on, but in our initial paper we when I get a letter from a physician in India and that he required open heart surgery. suggested that the subaortic obstruction or Pakistan saying, “Dear Professor, your On the morning of his operation, while I was caused by left ventricular hypertrophy. book is very important to me and we use it was doing a cardiac catheterization, a mes- These two patients led to our intense inter- constantly but I’d like to point out to you sage came down from the operating room est and further study of this condition. that on page 1372, in the second paragraph that my surgical colleague, Glenn Morrow, We used all of the tremendous opportu- in the left column, you say that this drug wanted to see me in the OR immediately. It nities at the NIH to study these, and many causes hypotension. With all due respect, was a little awkward because I had a patient other, patients by the best imaging tech- sir, it causes hypertension.” And so, what on the table. I came into the operating room niques that were then available, though pret- does that mean? It means that the book and Morrow was bent over the patient, and ty crude by today’s standards. We reported provides the capacity to reach out to many he said, “You know, Gene, you’ve screwed up. that the condition was frequently familial, more people than you can reach when you He doesn’t have a subaortic stenosis. I arrest- associated with sudden death, and most stand before a class. By the way, those letters, ed his heart,” which was a big deal at the time interestingly, we found that the obstruction of which I have received hundreds over the and quite risky. He opened the aorta, and put was dynamic. Any influence that reduced years, are usually correct, and the text is cor- his index finger through the aortic leaflets, the size of the ventricle, such as β-adrenergic rected with thanks to the letter writer. down into the body of the left ventricle. With agonists, intensified the obstruction. And, JCI: Have you ever given a thought to a his left hand, he put his fingers through the any intervention that increased the size of different career, or was it always medicine left atrial appendage through the left atrial the ventricle, such as raising the blood pres- and always cardiology? cavity, and into the left ventricle, and his two sure, reduced the obstruction. Beta blockers Braunwald: Yes, it has because I’ve always index fingers met in the left ventricle. There were just developed, and we were able to show really been challenged by the wide variety of was no obstruction! that they reduced obstruction and improved things that I’ve been able to do. In addition I was shocked and confused and blurted, exercise tolerance. Now, about 55 years later, to research, teaching, and textbook editing, “I don’t know what happened but I have a beta blockers remain a mainstay of therapy. I have also enjoyed the practice of cardiol- patient on the cath table.” And, as I walked JCI: You’ve described your 13 years at ogy. I’ve been constantly stimulated, and I out of the OR, I said, “But Glenn, if you get NIH as a virtual Camelot. So, what moti- am as excited today about issues surround- his heart started again, please stick a needle vated you to take a job at UCSD helping ing myocardial ischemia and heart failure into the left ventricle to see if he still has a to found their department of medicine and as I was when I was introduced to them as pressure gradient.” Morrow came down a serve as its first chair? a medical student more than 60 years ago! couple of hours later to say that when he Braunwald: I became a little restless. restarted the heart he confirmed a large And it’s like saying, “Well, I like steak. But, Ushma S. Neill

2 The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 1 January 2013