There is some uncertainty, and even controversy, as to when hypertrophic cardiomyopathy was first recognized. Dating back to 1868, there are autopsy-based case reports from France, Germany, and the United Kingdom composed of 1 or a few patients who appear to have died suddenly of a disease consistent in its features with hypertrophic cardiomyopathy. The 1959 and 1960 reports from London of Brock (clinical) and Teare (pathologic) are generally regarded as the first contemporary descriptions of hypertrophic cardiomyopathy. However, it is appropriate at this time to reflect on how and why this important disease was transformed from the subject of a few anecdotal case reports into a robust and treatable clinical entity ultimately regarded as a common genetic heart disease and the most frequent cause of sudden death in young individuals (including trained athletes).
In the early 1960s, a number of clinical investigators, largely in North America, most notably Dr. Douglas E. Wigle of Toronto General Hospital, made novel observations regarding outflow obstruction that contributed importantly to this transformation. However, it is undeniably the body of work of Dr. Eugene Braunwald and colleagues, particularly Dr. Andrew Glenn Morrow, at the National Institutes of Health (NIH) from 1958 to 1968, that is most responsible for the initial description of hypertrophic cardiomyopathy as a unique clinical entity (and its treatment, medical and surgical), culminating in the seminal 1964 American Heart Association (AHA) monograph in Circulation . That document is the first comprehensive description of hypertrophic cardiomyopathy, presented in 213 pages with 176 illustrative figures, 18 tables, and 191 references.
As part of this program at the NIH, the first patient with hypertrophic cardiomyopathy was diagnosed on clinical examination by Dr. Braunwald, and this disease, initially described in the context of dynamic obstruction of left ventricular outflow, was expanded to a broader spectrum to include the nonobstructive form. Also, in a remarkable twist, using only auscultation, Dr. Braunwald diagnosed his close friend and colleague, Dr. Andrew G. Morrow, the very individual responsible for designing the myotomy-myectomy operation that is still used today (referred to in the following discussion as “myectomy”), as having that same disease.
It is now 53 years since Morrow and Braunwald’s initial report, and Dr. Braunwald’s numerous seminal accomplishments, authoring more than 1,400 reports in diverse areas of cardiovascular medicine—prominently including coronary atherosclerosis and the pathophysiology of acute coronary syndromes (which continue to this day) —are well recognized and unnecessary to replicate in any detail here. What is particularly relevant to the present discussion is Dr. Braunwald’s intellectual attachment to the era at the NIH so early in his professional life, which he regards as perhaps the most creative in his long career, that included the early description of the disease he called idiopathic hypertrophic subaortic stenosis and which we (and he) now refer to as hypertrophic cardiomyopathy.
For these reasons, it seems very appropriate to discuss with Dr. Braunwald his recollections of those unique days when the NIH was a premier clinical cardiovascular research center. The purpose here is not only to formulate recollections but also to gain insights into the mechanisms and circumstances by which novel clinical research discoveries actually occur, in this case the description of a new and complex cardiac disease. Potentially, these principles and lessons will prove useful to future investigators who unexpectedly make observations for which there is no previous context. This conversation took place in Dr. Braunwald’s office in the TIMI Study Group at Brigham and Women’s Hospital in Boston, Massachusetts, on October 6, 2011.
The Beginning
Dr. Maron: Dr. Braunwald, thank you for allowing me to come here today and help you tell the story of the “birth” of hypertrophic cardiomyopathy in the late 1950s and early 1960s. The place is the Clinical Center at the National Institutes of Health in Bethesda, Maryland. When you started your observations on hypertrophic cardiomyopathy, you were only 28 years old, I guess, and the NIH Clinical Center and the cardiology and surgical branches were brand new. There were really no senior people. In fact, everyone was young, right?
Dr. Braunwald: That’s right, and at 28, I was one of the “older” guys. But I was 22 when I graduated from medical school, so I was 6 years postgraduate. Actually, I first came to NIH in 1955 and then went to The Johns Hopkins Hospital to finish my medical residency.
Soon after coming back to NIH in June 1958, the first patient, E.Z., a 27-year-old man from Saskatoon, was admitted to the Clinical Center. He had moderately severe angina pectoris and a loud holosystolic murmur at the apex of the heart and along the sternal border. Glenn Morrow, the chief of cardiac surgery, carried out a transbronchial left-heart catheterization. I was responsible for balancing the strain gauges that we used for pressure measurements, and for recording the tracings, but to me the most exciting task was analyzing the pressure tracings. The patient had a left intraventricular peak pressure gradient of 74 mm Hg, and we thought that he had a congenital subaortic stenotic membrane. Since his angina had progressed and he had severe obstruction, we scheduled him for surgery. At the time, cardioplegia was inducted with potassium citrate to arrest the heart.
During the operation, Glenn Morrow called me from the catheterization laboratory to come to the OR (operating room) immediately. When I arrived, he was very upset, telling me that the operation was a “royal screw-up.” Open-heart surgery was anything but routine in those days. This was one of the early open operations at the Clinical Center. Glenn’s voice was high pitched: “I opened the aorta and I stuck my finger into the ventricle and there was no obstruction!” He yelled, “Gene, I can’t feel anything wrong! I can’t see anything. What have you done? What the hell is going on here?” I thought, “How could this be? I didn’t know anything about gradients without obstruction. Maybe I made some terrible mistake with the pressure gauges or the multichannel recorder. Did I not balance the gauges properly?” I couldn’t imagine. I said, “Glenn, I must go back to the cath lab, because I left a patient on the table with a first-year fellow. If you can get his heart started, and take him off bypass, please measure the left ventricular pressure and see if he has a gradient.” That was a big “if” at the time. When a patient was placed on bypass, and the heart was arrested and the surgeon didn’t fix the problem, the patient was worse off and at high risk of death. Well, fortunately Glenn restarted the heart and got the patient off bypass successfully.
Glenn came down from the OR and walked into my office. I did not yet know the outcome. I was shaking with fear, but he was now very friendly and apologetic about his outburst and said that in fact that there was a high pressure gradient present after he had restarted the heart. He also told me that although there was no palpable or visual obstruction in the arrested heart, he did think that the left ventricle was thickened. Fortunately, the patient recovered uneventfully. We couldn’t figure the whole thing out. The patient had a loud heart murmur, and a high pressure gradient in the left ventricular outflow tract, but no obstruction in the arrested heart. After about 2 or 3 weeks of talking about this patient every day, Glenn said “Look, Gene. I’ve been in medicine longer than you have.” He was only 35 at the time. “Sometimes you come across something that you can’t explain, and you just have to move on.” A couple of months later, we had a similar experience with a second patient, and agreed then that we probably had something new here.
I was rereading this 1959 paper last night in preparation for this conversation, and I think that what I was pleased to see is this paragraph on page 186. I’ll let you read it.
Dr. Maron: Yes, you describe obstruction here: “The hemodynamic evidence of obstruction to left ventricular outflow is unequivocal; in the first 2 patients a systolic pressure difference between left ventricle and aorta was demonstrated on 2 separate occasions and was definitely localized to an area within the ventricle…none of the usual forms of aortic stenosis were present.…In these 2 patients it must be concluded that the obstruction…can only be explained by muscular hypertrophy of the left outflow tract of sufficient severity that flow is actually impeded during contraction.”
Dr. Braunwald: Yes, I think we pretty much nailed it. We knew there was an obstruction, and that it was due to the left ventricular hypertrophy. We proposed that these patients had muscular subaortic obstruction.
Dr. Maron: Absolutely. The key word is “impedance.” That observation was made in what could be regarded as the era of awakening in cardiovascular hemodynamics and pathophysiology. That was the beginning. Now, let me ask you about the original Morrow procedure for obstructive hypertrophic cardiomyopathy (surgical resection of muscle from the upper portion of ventricular septum). I assume that the collaboration and design was between you and Andy Morrow.
Dr. Braunwald: Yes, we talked about it a lot. But he led the conversations and developed the procedure. I was an intensely interested spectator in the operating room during the first few cases. Interestingly, Kirklin and Ellis began a surgical program almost simultaneously at the Mayo Clinic.
Dr. Maron: So, it’s interesting that the correct operation was designed without knowing the precise mechanism by which impedance to outflow occurred. The true mechanism of obstruction due to SAM (systolic anterior motion of the mitral valve) came along later, perhaps 1969, right?
Dr. Braunwald: Yes, it was after I left the NIH in 1968. But as early as 1960, Glenn felt the muscular obstruction grabbing his forefinger when he inserted it into the left ventricular outflow tract of the beating heart. Often in medicine, we come upon something that works, and we don’t really understand it yet, but we gradually understand the mechanism.
Dr. Maron: This is a great example of that principle.
We Are Onto Something Important
Dr. Maron: There was a lot of serendipity in this whole thing.
Dr. Braunwald: Yes, also a lot of luck.
Dr. Maron: We talked about the E.Z. operation and the first 2 patients, but when did you really think you knew? When did you get to that point? Was there anxiety and doubt that maybe this whole thing was not what you thought it is, and maybe that explains why hardly anyone else knew what you knew?
Dr. Braunwald: Over the next 2 years, we began to feel that we were onto something that was much more important—very exciting, but quite infrequent. What we didn’t suspect in our early experience was that hypertrophic cardiomyopathy was going to be so common and so important.
Dr. Maron: That’s interesting because when I started with hypertrophic cardiomyopathy in about 1975, we also thought of it as rare. Now, we understand it to be the most common of the genetic heart diseases, occurring in 1 in 500 of the general population, with at least 600,000 Americans affected.
Dr. Braunwald: As open-heart surgery developed and became more frequent, we identified an increasing number of cases, and by 1960 we described an additional 12 patients. That is also the paper in which we described the familial nature of the condition. So the pieces gradually came together. We were energized by the study of these patients and became even more excited as the years went on ( Figures 1 and 2 ) . In 1962, we described a group of patients who had left ventricular hypertrophy similar to those with obstructive hypertrophic cardiomyopathy, but without obstruction.
In that year, we also published an editorial entitled: “Hypertrophic Subaortic Stenosis: A Broadened Concept.” The idea behind the “broadened concept” was that there are patients with hypertrophic cardiomyopathy who had obstruction all of the time. They may have close relatives with left ventricular hypertrophy who never had obstruction, and there were patients who had obstruction some of the time. In 1963, the editor of Circulation invited Glenn and me to prepare the monograph, which was published as a supplement in 1964. More and more patients with hypertrophic cardiomyopathy were being reported from all over the world. Doug Wigle’s group at the University of Toronto and John Goodwin and his colleagues at Hammersmith Hospital in London made the most important contributions.
We Are Onto Something Important
Dr. Maron: There was a lot of serendipity in this whole thing.
Dr. Braunwald: Yes, also a lot of luck.
Dr. Maron: We talked about the E.Z. operation and the first 2 patients, but when did you really think you knew? When did you get to that point? Was there anxiety and doubt that maybe this whole thing was not what you thought it is, and maybe that explains why hardly anyone else knew what you knew?
Dr. Braunwald: Over the next 2 years, we began to feel that we were onto something that was much more important—very exciting, but quite infrequent. What we didn’t suspect in our early experience was that hypertrophic cardiomyopathy was going to be so common and so important.
Dr. Maron: That’s interesting because when I started with hypertrophic cardiomyopathy in about 1975, we also thought of it as rare. Now, we understand it to be the most common of the genetic heart diseases, occurring in 1 in 500 of the general population, with at least 600,000 Americans affected.
Dr. Braunwald: As open-heart surgery developed and became more frequent, we identified an increasing number of cases, and by 1960 we described an additional 12 patients. That is also the paper in which we described the familial nature of the condition. So the pieces gradually came together. We were energized by the study of these patients and became even more excited as the years went on ( Figures 1 and 2 ) . In 1962, we described a group of patients who had left ventricular hypertrophy similar to those with obstructive hypertrophic cardiomyopathy, but without obstruction.
In that year, we also published an editorial entitled: “Hypertrophic Subaortic Stenosis: A Broadened Concept.” The idea behind the “broadened concept” was that there are patients with hypertrophic cardiomyopathy who had obstruction all of the time. They may have close relatives with left ventricular hypertrophy who never had obstruction, and there were patients who had obstruction some of the time. In 1963, the editor of Circulation invited Glenn and me to prepare the monograph, which was published as a supplement in 1964. More and more patients with hypertrophic cardiomyopathy were being reported from all over the world. Doug Wigle’s group at the University of Toronto and John Goodwin and his colleagues at Hammersmith Hospital in London made the most important contributions.
Dynamic Obstruction
Dr. Maron: One of the most interesting and distinguishing features of hypertrophic cardiomyopathy is the dynamic nature of the outflow obstruction. How did that discovery come about?
Dr. Braunwald: Actually, it was quite serendipitous. We were studying the effects of intravenous ouabain on the hemodynamics of patients with severe valvular aortic stenosis and other patients with hypertrophic cardiomyopathy. We observed intensification of the intraventricular pressure gradient with the glycoside. An important coinvestigator on this study was Bob Frye, who went on to a dazzling career at the Mayo Clinic, first as chair of cardiology and then of medicine. After this observation with ouabain, we immediately went on to study a more powerful inotropic agent, the β-adrenergic agent isoproterenol, and found the same thing. We also studied the α-adrenergic agonist methoxamine, a pure vasoconstrictor, and found that the obstruction could be eliminated transiently.
In addition, we found that in patients with hypertrophic cardiomyopathy, in the beat after a premature ventricular contraction, the arterial pressure fails to show a normal increase in pulse pressure. This phenomenon, which is quite accurate in recognizing hypertrophic cardiomyopathy, is called the “Brockenbrough sign,” named for Ned Brockenbrough, a research fellow rotating through the catheterization laboratory, who first authored this paper. We observed and reported the development of sudden cardiac death, a complication that sometimes occurred in patients with little or no obstruction. We also commented on the great variability of the clinical course of hypertrophic cardiomyopathy.
Other hemodynamic observations that led to provocation or intensification of the pressure gradient were reductions of preload with nitroglycerin during the strain of the Valsalva maneuver, during tachycardia, and on assuming the erect posture. We also showed slowed ventricular filling, i.e., diastolic dysfunction, that was presumably due to reduced left ventricular compliance. Putting these and other observations together, we postulated that the reduction of left ventricular volume, however produced, provoked or intensified obstruction, and that increases in ventricular volume have the opposite effect.
Beta Blockade
Dr. Maron: For a long time, β blockers were essentially the only nonsurgical treatment available for hypertrophic cardiomyopathy. It remains a mainstay in the treatment of the disease to this day. I suspect you were responsible for the development of β-adrenergic blockade in hypertrophic cardiomyopathy? Can you elaborate on that?
Dr. Braunwald: In 1962, the late James Black described the first β-adrenergic blocker, pronethalol, and shortly thereafter, I met him in London, where I was participating in one of the first international hypertrophic cardiomyopathy meetings. I described the condition to him and the intensification of obstruction with isoproterenol, as well as with muscular exercise. I asked him if we could get the drug—it was not yet available—and he graciously agreed. Interestingly, in 1988, Black received a Nobel Prize for that discovery. Immediately after my return, we administered intravenous pronethalol to patients with hypertrophic cardiomyopathy, and we noted that, as expected, it blocked the provocation or intensification of obstruction with isoproterenol. We were also excited to note that it also reduced the intensification of obstruction during exercise. The paper’s first author was Don Harrison, who went on to become chief of cardiology at Stanford and president of the American Heart Association.
Naturally, we saw β blockade as a potential treatment for patients with hypertrophic cardiomyopathy. When oral propranolol became available, we conducted a placebo-controlled study, which showed that the anginal threshold in these patients (as assessed by treadmill exercise) was markedly increased. We found that symptomatic benefit was sustained on propranolol in some patients with angina and that surgical treatment could be averted, or at least postponed. The lead author of these 2 papers was Lawrence S. Cohen, who went on to become chief of cardiology at Yale.
Dr. Maron: When did you leave the NIH—and hypertrophic cardiomyopathy?
Dr. Braunwald: It was 1968, and in that year, I published my last paper on hypertrophic cardiomyopathy, in which Stuart Frank and I reviewed the natural history in 126 patients.
Dr. Maron: 1958 to 1968, 10 years. What stands out is the confidence and lack of doubt, and maybe that’s the message. If you want to be an innovative clinical investigator, great confidence is a requisite.
Dr. Braunwald: How about a dash of youthful arrogance thrown in? No, I wouldn’t be as certain today if I made findings like those I made a half century ago. I am much more cautious today, probably because I have been “bitten” a few times. Of course, the whole Criley episode…
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