Reflections on Six Decades of Hypertrophic Cardiomyopathy From Eugene Braunwald

On October 16 to 18, 2021, the 3-day 7th International Summit of Hypertrophic Cardiomyopathy was held virtually with almost 700 registrants and faculty from 40 countries and 42 states (Drs. Martin and Barry Maron, Directors). This meeting, the largest for this disease, was an opportunity to engage on a wide variety of topics with insights relevant to hypertrophic cardiomyopathy provided by 47 lectures, debates, and comprehensive discussions from 36 distinguished international speakers, including Dr. Eugene Braunwald. On October 16 to 18, 2021, the 3-day 7th International Summit of Hypertrophic Cardiomyopathy was held virtually with almost 700 registrants and faculty from 40 countries and 42 states (Drs. Martin and Barry Maron, Directors). This meeting, the largest for this disease, was an opportunity to engage on a wide variety of topics with insights relevant to hypertrophic cardiomyopathy provided by 47 lectures, debates, and comprehensive discussions from 36 distinguished international speakers, including Dr. Eugene Braunwald. A particularly notable part of this program was an interview with Dr. Eugene Braunwald conducted by Dr. Barry Maron. These 2 investigators have had an intimate long-term relation with hypertrophic cardiomyopathy spanning 60 and 50 years, respectively. Dr. Braunwald provided unique reflections on hypertrophic cardiomyopathy (past, present, and future) including on his own initial comprehensive and seminal description of this new disease in the early 1960s that he called idiopathic hypertrophic subaortic stenosis (IHSS). Therefore, presented here for the AJC readership are both the text and video of Dr. Braunwald's interview. Barry J. Maron, (B.J.M.): “Dr. Braunwald (Gene) I want to welcome you to the 7th International HCM Summit. An HCM Summit would not be complete without you. You don't need any introduction, obviously, as you are arguably the most important cardiologist of our era; but what a lot of people out there, I assume, don't know (particularly the younger ones) is that you are in fact the “father” of HCM, which you called IHSS during that era. And as part of that look backward, this is your famous AHA monograph. The first 64 patients are reported in detail (214 pages) and it is the first comprehensive description of the disease. So, this will always be a landmark, substantiating your seminal contributions to this disease. Certainly, the hardest thing to do is to describe a disease for the first time. I don't think there are too many people that could have done that. Clinical investigators like myself can only take your initial contributions and expand on them.” Eugene Braunwald (E.B.): “Well, Barry, you said some, very, very nice things about me. They are somewhat exaggerated. It's a pleasure and an honor to be participating in this superb symposium.” B.J.M: “Well, we appreciate it as well. I know there are some things you want to talk about and we want you to talk about. So let me trigger those ideas. In your view, when was hypertrophic cardiomyopathy, or whatever we want to call it, initially identified and then as part of that, what was your first encounter with the disease?” E.B.: “Well, it's very hard to be first in anything because as you look at the HCM literature, you see that people already had some ideas about this condition. There were 3 papers in the mid-19th century from Paris that described patients who at postmortem had unexplained left ventricular hypertrophy. One of these was seen during life, a woman with a heart murmur. So, they were beginning to do auscultation. So, they described a patient with a heart murmur and cardiac hypertrophy. They didn't know what they were looking at but they recorded it, and the findings are consistent with HCM. “And there were scattered reports in the early 20th century. If you look at the totality of the picture, there would be pieces of HCM. For example, a couple of case reports of young persons who died suddenly and at postmortem had a hypertrophied left ventricle. There were several reports of familial cardiomyopathies. We may have been able to wrap something around these cases because the components of HCM were present. An important study by Teare, an English pathologist, described 9 cases which showed the pathologic features of HCM. “Our first patient was a 27-year-old Canadian man who had angina and exertional dyspnea for a number of years and was known to have had a heart murmur. He came to us in June 1958. At left heart catheterization, he had a gradient in the 70s in the left ventricular outflow tract. He was quite symptomatic, and we thought…‘we’ being Glenn Morrow, Chief of Cardiac Surgery at the NIH, and I…we thought that he had a rare congenital anomaly, namely membranous subaortic stenosis. It was in the very early days of open-heart surgery and relief of that obstruction seemed like a fairly simple procedure that didn't require valve replacement or extensive surgery. “I was head of the catheterization laboratory at the NIH at the time, and on the morning of this patient's operation, I got a call that was picked up by the nurse in the cath lab: ‘Dr. Morrow wants to see you in the operating room.’ And I said, ‘Please tell him I'm doing a case and I'll be up there as soon as I can but I'm just starting.’ So she said, ‘No, he wants you up there now, and you better get up there!’ “So I went up to the operating room, and it was chaotic. Open heart surgery at that time was like sending a man to the moon. Dozens of people were there—anesthesiologists, perfusionists, assistant surgeons, nurses, visitors, administrators, etc. “So Glenn is in there, obviously very nervous, and he barked: ‘Gene, there is no obstruction. You screwed up!’ I'm taken aback. I said, ‘Well, you know he had a gradient of 74 mm of mercury, and that's for real.’ He said, ‘Well, there is no obstruction.’ He placed a finger through the aortic orifice into the left ventricular cavity. Then he had an assistant make an incision in the left atrium, placed his other forefinger into the left atrium and advanced it into the left ventricle; the two fingers met. He said, ‘Now do you believe me that there's no obstruction?’ I replied, ‘I don't know what to say.’ And I was very upset about it. The patient's heart had been arrested with potassium citrate. Open heart surgery was so primitive in those days that if you didn't fix the lesion, the mortality was significant just from the thoracotomy, placing the patient on cardiopulmonary bypass and stopping the heart and then restarting it. “I left the operating room with my tail between my legs. But I had one thought in this whole embarrassing situation. I said just before leaving: ‘Glenn, if you are able to restart the heart, please stick a needle into the left ventricular cavity and measure the pressure.’ He had a radial artery line. And I walked out and was too upset to continue my case in the catheterization laboratory. “A couple of hours later I was still fretting. Glenn came down from the operating room and seemed relaxed and friendly. He patted me on the shoulder and said, ‘It's going to be okay. The boy is doing fine.’ The ‘boy’ was just 2 years younger than I was. I said, ‘Did you measure the left ventricular systolic pressure?’ He said, ‘It was 200 millimeters of mercury.’ ‘What was the arterial pressure?’ He said, ‘About 100.’ So I said, ‘What do you think is going on?’ He replied, ‘Beats me.’ I said, ‘Did you notice anything unusual at all?’ He said, ‘Well, the left ventricle was thick but that shouldn't cause it.’ “So that's where we were, quite confused, and we talked about the patient, who fortunately made an uneventful recovery but of course still had a loud systolic murmur. We were trying to figure out what was going on in his heart.” B.J.M.: “You were young, much younger than would be the case now.” E.B.: “That's right. We continued to discuss the patient. Finally, Glenn said to me, ‘Look, we're just going around in circles. Let's put this case on ice for now. There's more important things to be done.’ And I agreed. And that's the way it was for a couple of weeks. And then a second patient appeared with exactly the same clinical findings, who also was a man in his twenties. But now we were alerted to this. And after the exploratory cardiotomy we brought him back for a left ventricular angiogram, in which we saw the thickness of the left ventricle and an obstruction to left ventricular outflow. I now think it probably was the anterior mitral valve leaflet which we didn't recognize at the time. “We reported these 2 patients in Circulation1Morrow AG Braunwald E. Functional aortic stenosis, a malformation characterized by resistance to left ventricular outflow without anatomic obstruction.Circulation. 1959; 20: 181-189Crossref PubMed Scopus (68) Google Scholar and concluded that muscular hypertrophy caused the obstruction. There was a lot of communication going on between cardiac surgeons about this as open-heart surgery was developing rapidly; people were getting to see these patients.” B.J.M.: “When did you actually realize you were embarking on something that was going to turn out to be big?” E.B.: “About a year after we saw these initial 2 patients. The observations on them were made in 1958; our paper was published in 1959; and in 1960, we had 14 cases. Among them were 2 families, so we now had a disease that was genetic with autosomal dominant transmission in some cases, with some instances of sudden death. It was beginning to take shape as an entity. “We were now on the lookout for more patients, and we heard about cases in Toronto, Mayo Clinic, 2 separate groups in London, and we were communicating with one another.” B.J.M.: “It took off.” E.B.: “Yes.” B.J.M.: “And how did that happen?” E.B.: “We published several papers describing our findings and in 1964, the monograph which was a Supplement in Circulation (2).” B.J.M.: “You didn't let it go. When did it start to become a new disease?” E.B.: “Well, I think that when we filled in a number of the blanks.” B.J.M.: “I understand.” E.B.: “I think that one of the things that had me personally very excited was the variability of obstruction—dynamic obstruction.” B.J.M.: “Right.” E.B.: “It came about in 2 ways. We had several patients who, for some reason, were catheterized twice; the obstruction was quite different. We have one such patient illustrated in the monograph2Braunwald E Lambrew CT Rockoff SD Ross Jr, J Morrow AG. Idiopathic hypertrophic subaortic stenosis. I. A description of the disease based upon an analysis of 64 patients.Circulation. 1964; 30: 3-119PubMed Google Scholar who showed no gradient at all at the first catheterization, and 3 days later, a gradient of about 50 millimeters of mercury. So, we were seeing huge variations in obstruction. The second clue to dynamic obstruction was also serendipitous. We were conducting a study in the cath lab on the effects of intravenous ouabain in patients with left ventricular outflow obstruction irrespective of whether it was muscular or valvular. And we found a patient with HCM and a pressure gradient that was about 60 millimeters of mercury, as I recall. We gave this young man ouabain. Well, the gradient rose markedly. We were quite nervous about it because his arterial pressure fell. We gave him fluids and watched him carefully in the laboratory. He did perfectly well. So, we were getting the idea: ‘Well, something is increasing the obstruction. This is a positive inotropic effect.’ So that got us into using isoproterenol in the catheterization lab since it is a more powerful inotrope than ouabain, and it was enormously helpful in intensifying or provoking obstruction.3Braunwald E Ebert PA. Hemogynamic alterations in idiopathic hypertrophic subaortic stenosis induced by sympathomimetic drugs.Am J Cardiol. 1962; 10: 489-495Abstract Full Text PDF PubMed Scopus (85) Google Scholar” B.J.M: “Yes. Related to this, a lot of people do not recognize that you were actually the first to describe the nonobstructive form of HCM.” E.B.: “Yes, we did.4Braunwald E Aygen MM. Idiopathic myocardial hypertrophy without congestive heart failure or obstruction to blood flow. Clinical, hemodynamic and angiocardiographic studies in fourteen patients.Am J Med. 1963; 35: 7-19Abstract Full Text PDF PubMed Scopus (28) Google Scholar” B.J.M.: “Can you address that? The true nonobstructives.” E.B.: “Yes. What we had started with was what I would call the centerpiece of HCM. These were patients with left ventricular hypertrophy and obstruction in the basal state. Then we recognized patients with left ventricular hypertrophy with no obstruction in the basal state who were first degree relatives of patients with severe obstruction. Then there were patients with left ventricular hypertrophy but no obstruction in the basal state but provokable obstruction with isoproterenol. Then we get to patients with left ventricular hypertrophy, a positive family history, but in whom obstruction can't be provoked! So, we recognized a wide spectrum in the dynamics of outflow tract obstruction in HCM.5Braunwald E Brockenbrough EC Morrow AG. Hypertrophic subaortic stenosis – a broadened concept.Circulation. 1962; 26: 161-165Crossref PubMed Google Scholar” B.J.M.: “Yes. So, you really had the whole thing put together. This was classic clinical investigation. I don't know whether we have that anymore. The ability to deal with clinical facts and put them together in a novel way that makes sense for a disease spectrum and the individual affected patients. There is so much now about genetic markers and biomarkers and dedication to statistical models and group data as the ultimate and only truths. This was, in fact, a classic example of understanding human physiology and interaction with what was a new and evolving disease.” E.B.: “Well, I think I need to add a couple things. First, I must give my late partner Glenn Morrow full credit. He developed an operation (myectomy) that is still widely used and very successful.6Morrow AG Brockenbrough EC. Surgical treatment of idiopathic hypertrophic subaortic stenosis: technic and hemodynamic results of subaortic ventriculomyotomy.Ann Surg. 1961; 154: 181-189Crossref PubMed Scopus (158) Google Scholar He was also involved in many of the ideas and measurements that we made. This was a true partnership. “The other point is that we recognized that many patients with HCM had diastolic dysfunction.7Stewart S Mason DT Braunwald E. Impaired rate of left ventricular filling in idiopathic hypertrophic subaortic stenosis and valvular aortic stenosis.Circulation. 1968; 37: 8-14Crossref PubMed Scopus (102) Google Scholar This was an early foray into heart failure with preserved ejection fraction, which we now know is common in HCM.” B.J.M.: “It's a different era. Your contributions were in creating an understanding of cardiac physiology. Those principles were actually new in the early 60s. We take that for granted now, obviously. All of this is part of your contribution over 60 years. For sure, a lot has been done.” E.B.: “And, and a lot of it has been from you and your team.8” B.J.M.: “I wasn't actually looking for a compliment, but I will accept it. “What do you see about the future, given everything that has happened in 60 years, and the disease pretty well described now, including management? You know, this wouldn't have happened, at least not in the same way without you. But now, looking forward, what do you think?” E.B.: “Well, there are a couple of things that puzzle me. We have a familial form and a nonfamilial form of HCM. I would like to know a little more about the nonfamilial form. What is it? What is the molecular basis of the disease in these patients? Why do they have left ventricular hypertrophy? Why is the hypertrophy in many patients associated with severe obstruction, but they have no affected family members and there are no genetic findings? So, what's going on with them? That's a huge issue. These patients represent more than half of the patients with HCM. How do we counsel them?” B.J.M.: “Yes. This is a particularly important point that is emerging now. What actually causes hypertrophic cardiomyopathy? The disease has acquired a reputation over the last 30 years as a uniformly genetic condition (autosomal dominant), due to mutant genes encoding proteins of the cardiac sarcomere. However, it is also clear now that this represents an oversimplification of a complex disease with many cases that are obviously nongenetic and nonfamilial. Indeed, most patients (70%) with established disease do not have a pathogenic (disease-causing) sarcomere mutation and many of the morphologic features of hypertrophic cardiomyopathy are not associated with the sarcomere, such as the elongated mitral valve responsible for obstruction. The monogenic model is not going to be able to explain this disease in its entirety.” E.B.: “You're correct. It does not. I saw your recent paper in JACC addressing this issue. That was dynamite.” B.J.M.: “Thank you. The monogenic hypothesis for hypertrophic cardiomyopathy is more than 30 years old, but that does not mean we are with it So after 60 years, in a we are back to where we started because we really don't what the true is for all patients with this B.J.M.: you with that E.B.: “Yes. That to be the but we have a deal about this and you have us a B.J.M.: “I For sure, the clinical in and treatment have been in and mortality and increasing you have any about E.B.: “I left the of in to become of at of and then at the This didn't me much time to one and the one I was but in I think I have up an HCM in I did see a lot of patients with HCM in my but I didn't do any a lot of the of the was out at the and I had the opportunity to that B.J.M.: “You me that you had a that you an opportunity to to hypertrophic cardiomyopathy in the E.B.: “Yes. You a very important in of HCM. the group that I left in at NIH in obviously B.J.M.: “So is there anything you would like to talk about or E.B.: “I know there's been a lot of in What is its it be started at a very early of the hypertrophy, at the of about years and the of the B.J.M.: “What do you think the would E.B.: “Well, it the of B.J.M.: “Well, we have 40 years since we had a new for HCM and it does that will be and However, it is a inotrope for disease to the outflow E.B.: “Yes.” B.J.M.: “So I think there's a that a like or other will make a It's just a of what it makes and at what E.B.: that there are HCM like that have a of patients, it be much to address like this than it would have been or years B.J.M.: “The way I think most of us look at if there's something new that some patients, that is a E.B.: “Yes.” B.J.M.: the other hypertrophic cardiomyopathy is a disease and simple are hard to So, I think we can it at E.B.: “Well, I think we people to be about the of new than what's been done several B.J.M.: “Yes. We could more investigators in this disease but with novel insights by There are way too many papers published that only the “Dr. we all appreciate your time here but more than that, your contributions to hypertrophic cardiomyopathy, but also to disease We here on your Clinical course and of hypertrophic J Med. PubMed Scopus Google Scholar you have me it E.B.: “Thank you very The video of Dr. Braunwald's interview can be with the The that they have no known or that could have appeared to the reported in this