HomeCirculationVol. 144, No. 21A Foot Soldier in Cardiac Metabolism: A Conversation With Heinrich Taegtmeyer, MD, DPhil Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBA Foot Soldier in Cardiac Metabolism: A Conversation With Heinrich Taegtmeyer, MD, DPhil Maryjane Farr, MD, MSc Maryjane FarrMaryjane Farr https://orcid.org/0000-0003-1066-9368 Search for more papers by this author Originally published22 Nov 2021https://doi.org/10.1161/CIRCULATIONAHA.121.058019Circulation. 2021;144:1659–1663Dr Heinrich Taegtmeyer grew up in post–World War II Germany and received his Dr med from the University of Freiburg, Germany, in 1968. He wrote a dissertation on cellular electrophysiology in the laboratory of Professor Albrecht Fleckenstein, who discovered calcium antagonists. Dr Taegtmeyer continued his training at Boston City Hospital, followed by a cardiovascular fellowship at the Peter Bent Brigham Hospital. He then completed a DPhil in Biochemistry at the University of Oxford, United Kingdom, and his dissertation focused on cardiac metabolism. Dr Taegtmeyer was one of the last students to work with Professor Hans Krebs.Dr Taegtmeyer has been at the University of Texas Health Science Center at Houston since 1982. His research on cardiac metabolism has received National Institutes of Health funding for >45 years. Here, he talks with us regarding the history of the investigation of cardiac metabolism, his important mentors and sponsors, and his impressions on contemporary concepts of metabolic approaches to reverse myocardial dysfunction.Dr Farr asks: Please tell us about your early life in Germany.Dr Taegtmeyer replies: I grew up in northern Germany after World War II. My parents sent me to a classical high school. After the obligatory military service, I was admitted to medical school in Freiburg, which is in southern Germany. There, I started my journey in cardiovascular research with a dissertation project in cellular electrophysiology. The department head was Professor Albrecht Fleckenstein. Fleckenstein, known for his discovery of calcium antagonists, was an imposing figure, both in physical stature and in temperament. He was also a brilliantly engaging teacher who gave the main physiology lecture 5 days a week. More than that, it impressed me how Fleckenstein’s research fueled his teaching, and, vice versa, his teaching also fueled his research.Download figureDownload PowerPointHeinrich Taegtmeyer, MD, DPhilFifty years ago, the word “mentor” was an unknown term. Closest to it in the German language was the term “Doktorvater,” literally translated “father of the dissertation.” This needs an explanation. In the German academic system, the degree Dr med is awarded to those students who graduate from medical school after defending a dissertation. My Doktorvater was Dr Hermann Antoni, one of the younger faculty members. He and I quite literally worked side by side in the lab. From the pulling of tiny microelectrodes to the harvesting of papillary muscles from a small nonhuman primate, from the construction of tissue baths to the recording of the actual experiments, we did everything together, with an increasing amount of responsibility shifted to me as time went by. The effort paid off. We made an unexpected discovery: hyperpolarization of papillary muscles conditioned them for spontaneous depolarizations—an unexpected observation that ultimately resulted in the discovery of a new potassium channel which can be blocked by a drug. My thesis received the Byk-Gulden Award from the university and an invitation for my wife and me to attend a private dinner with the dean.How did you get to Boston after completing your Dr med in Freiburg?Major decisions after graduating from medical school were based on my desire to complete the clinical training first, before embarking on further research. This was difficult in the German system, which placed a strong emphasis on research before reengaging in clinical activities. The opportunity came when I met Dr Ed Sonnenblick, who was lecturing in Germany, and who steered me to an opportunity to train in the United States. Through fortunate circumstances, I was accepted into the residency program of the storied 2&4 Medical Service at the Boston City Hospital (also known as the Harvard Medical Service). That, followed by a fellowship in cardiovascular medicine at the Peter Bent Brigham Hospital, set me firmly on the track of a physician–scientist and constituted the first turning point in my professional life. The fellowship at the Brigham was designed especially well to prepare fellows for a career in academic medicine by placing equal emphasis on clinical training and research at the bench.Tell us about your first experiments in cardiac metabolism with Mike Lesch.My fellowship at the Brigham directed me into the field of cardiac metabolism. I was assigned to Dr Mike Lesch, a young faculty member who took me into his small lab. Mike’s interest in metabolism was sparked by his mentor at Johns Hopkins, Dr Bill Nyhan, when Mike was a medical student. He and his mentor discovered an inborn error of metabolism, the Lesch-Nyhan syndrome, which, as you know, causes high uric acid levels and manifests as gouty arthritis, renal dysfunction, and self-mutilating behavior. Mike subsequently went into cardiology, joined the faculty at the Brigham, and studied the dynamics of protein turnover in the heart. Accordingly, my first paper with Mike was entitled “Thermoregulation of myocardial protein synthesis in rabbits.” Using a radioactive tracer technique, we “discovered” that the optimum temperature was 39.5oC. After the paper had been published, I learned from further literature study that the rabbit’s normal body temperature is 39.5oC. In hindsight, we could have saved ourselves a lot of work. Still, for me, it was a meaningful entry into a new field of research. It also primed me for a general interest in the theme “when discovery becomes rediscovery,” an issue of recent discussion to which I will return later. More importantly, Mike led me gently to a path of independence with a project centered on myocardial amino acid metabolism. Ultimately, this resulted in a single-author paper on succinate production by hypoxic papillary muscles1 and my first R01 grant from the National Institutes of Health.You were doing such great work in Boston. What made you leave for Oxford?By now enthusiastically attached to cardiology (I had passed my boards in 1977) and to metabolism, I became increasingly concerned that I still lacked many skills for a successful future as an investigator. This grounding I sought when I applied to the Krebs lab in Oxford. Krebs took me into his lab, but only after some hesitation. I vividly remember the interview he conducted, at short notice, during his layover at Logan Airport in Boston. I took a chance because Krebs had never shown much interest in the heart. We talked about my plans to study amino acid metabolism in isolated adult heart muscle cells. A week later Krebs rang me, this time from Oxford. After discussions with the senior members of his lab, he said, I would be welcome, but only if I brought my own support along. I took this advice quite literally because Krebs also suggested to bring my wife and our children to Oxford as well. And what was meant to be 6 months leave from Brigham (with Dr Braunwald’s blessings) turned into a full DPhil (PhD) with a much greater time commitment. The consequence was incalculable at the time. Ultimately, our 3 children graduated from university in England, and 2 of them are now British subjects.The days in the Metabolic Research Laboratory in Oxford (the Krebs Lab) were also a milestone in my professional life. The lab was squeezed between 2 medical wards at the back of the Radcliffe Infirmary. The Prof himself had his desk and his own bench space, alongside us students, postdocs, research assistants, and 4 senior scientists, including my immediate supervisor, Mr Reginald Hems. I owe each of them a deep measure of gratitude, especially Reg, who took me under his big wings and taught me all I needed to know in metabolic research. And that was a lot.Krebs was skeptical about my plan to isolate adult heart muscle cells and to study their amino acid metabolism. He insisted that I examine cardiac metabolism in the working heart, because, he argued, “isolated cells do not pump any blood.” So, he ordered Reg and me to redesign a perfusion system that fulfilled his criteria.2 The demand for this model system has remained undiminished. As an aside, our isolated working rat heart preparation has been readily adapted to the mouse heart, which has opened the door to assessing cardiac function and metabolism in a host of genetic models and to shedding light on some of the most vexing challenges in the metabolic control of cardiac function.What was your working conceptual framework of energy metabolism in the heart during this time?Initially, we were focused on the competition of different energy substrates providing fuel for the heart under different circumstances. We drew attention to the fact that fatty acid oxidation suppresses glucose oxidation, which was already known from the work of Dr Philip Randle, but learned that glucose also suppresses fatty acid oxidation (a “reverse Randle effect”). We also found that high physiologic workload negates the effect of insulin in the heart, and that ketone bodies, when presented as the only substrate to the heart, results in a failure of contraction, which is reversed by the addition of glucose, or lactate, or any anaplerotic substrate for the Krebs cycle. Collectively, those findings have made me increasingly aware of the interconnectedness of metabolic pathways and of the principle that in the heart, the transfer of energy is linked to a series of moiety-conserved cycles.2Then, as now, the principle is straightforward: The heart is an engine that converts stored chemical energy (fuels) into dynamic mechanical energy (pressure × volume work), very much like a car engine converts fuel into motion. But there is another dimension to metabolism that is often overlooked (Figure). Metabolism of energy-providing substrates (fuels) also provides the building blocks for proteins, nucleic acids, and phospholipids. The dynamic state of cell constituents includes enzymes, actin and myosin, mitochondria, histones, membranes, DNA, RNA, and even the purine nucleotide ring of ATP. In short, heart muscle cells renew themselves from within. We termed the whole process “intracellular self-renewal” when we described the simultaneous activation of pathways of protein synthesis and degradation in atrophic remodeling of the heart.3 Furthermore, current work in our lab has identified nonmetabolic functions of certain metabolites, such as glucose 6-phosphate and AMP, as regulators of cardiac growth and destruction.Download figureDownload PowerPointFigure. Dimensions of metabolism. LV indicates left ventricular.Can you characterize where you felt your place was in the growing field of cardiac metabolism during this time?By the time I left Oxford, I had acquired a significant skill set and deep respect for the complexities of intermediary metabolism. A few reflections are in order at this point. I have had the good fortune to be in personal contact with unusual scientists. What can be learned from teachers of great distinction? Most of all, they expect a high standard of research. I think we all measure ourselves by comparisons (the whole peer review system is built on such comparisons). In the absence of someone with outstanding ability, we easily overestimate ourselves.In contrast, talented people feel dwarfed in the company of giants, which, according to Krebs, is a most useful feeling. I see myself as a foot soldier in an army. The giants of science teach us to see ourselves modestly, and not to overrate ourselves. In metabolism, as in research in general, the primary aim is not to collect more and more facts, but facts of strategic value. Here, again, the peer review system and the collegiality of others with like-minded interests are irreplaceable. The key is a motivation to advance the field of research, and not so much to promote a career. Advancing a field needs enough space to be creative, to test new ideas, the tools to do so, and a critically receptive community of peers. In short, the right environment and the company we keep.You finish at Oxford. What was your first position as an assistant professor and principal investigator?After Oxford, I needed a job, and I found it in Houston, Texas, a place I had never even thought of. The University of Texas Medical School at Houston (now the McGovern Medical School) was founded in 1970 as part of the University of Texas System and was recruiting new faculty. The school offered ideal conditions for a physician–scientist. Located in the Texas Medical Center with many other esteemed institutions close by, including Baylor College of Medicine, the Texas Heart Institute, and the MD Anderson Cancer Center, I was assigned brand new lab space and an office adjacent to the lab. Both the hospital and clinic were only a few steps away, and I had access to the Positron Imaging Center (directed by Dr K. Lance Gould), with a brand-new cyclotron sitting in front of the building. Within a year and a half, I had built a small team and recruited my first 2 graduate students. Over the years, the size of the small lab fluctuated between 4 and 10 members, and a few years on, one of the graduate students called our lab “The Small Lab with Big Ideas.”Can you tell me about some of these Big Ideas?One of our first projects was the validation of FDG as a glucose tracer analog in the heart. Additional projects included understanding how anaplerosis of the Krebs cycle rescues contractile function of the working heart. The hemodynamically stressed heart preferentially oxidizes glycogen, and glycogen protects the heart from ischemic stress. Unloading the heart from hemodynamic stress reactivates the fetal gene program in the same way as increasing hemodynamic stress. Reverse remodeling of the failing heart can be induced by mechanical unloading (a phenomenon we termed the “molecular left ventricular assist device”). Nonmetabolic signaling functions of metabolites include nutrient-sensing pathways of cardiac growth. Metabolite signals also regulate cardiac atrophy (through AMP kinase). Metabolic remodeling precedes, triggers, and sustains functional and structural remodeling of the heart. Cardiometabolic stress in obesity and diabetes results in hypertrophy and heart failure. Unloading the heart from metabolic stress improves cardiac function. Insulin resistance protects the heart from metabolic stress. This has challenged a widely held dogma that insulin resistance induces heart failure.Looking back, I feel overwhelmed by the diversity of topics. There really is no aspect of cardiac physiology that is not touched by metabolism. Unity in diversity: assessing cardiac metabolism is also driven by a wide spectrum of experimental and analytical techniques, many of them enduring, others being added at a rapid pace. A few years ago, several of my colleagues and I prepared a resource document in the form of an American Heart Association Scientific Statement.4Let’s return to the concept of “when discovery becomes rediscovery.”In his book The Structure of Scientific Revolutions, Thomas Kuhn defines progress as an old paradigm that is replaced by a new paradigm. The rich history of cardiac metabolism has reason to challenge this notion. Two examples of rediscovery and of dediscovery from our own work may serve as an illustration. First, the “succinate story,” published in 1978,1 has been elegantly rediscovered and confirmed by several other labs since then. In more recent years, our concept of unloading the failing heart from metabolic stress has gained immense popularity with the introduction of the SGLT2 inhibitors. Second, we saw reason to demolish our own hypothesis that a return to the fetal gene program in the unloaded heart promotes reverse remodeling (“healing”) of the failing heart when we observed that the fetal gene program is already fully activated in the failing heart.5Talk with me about your impressions on the modern-day physician–scientist.It has been said that the physician–scientist is an endangered species. Beyond doubt, the leaders of American medicine are accomplished physician–scientists. Yet most physician–scientists belong to the double-hyphenated group of “foot soldier–physician–scientists.” Woe to any one of them when the grant does not get funded. Woe to them when a patient asks: “Are you a PhD? I don’t want to be your guinea pig.” Programs that develop and sustain physician–scientists vary from institution to institution. There is a lot of room for improvement, because physician–scientists are the lifeblood of translational medicine, like primary care physicians are the lifeblood of clinical medicine.The most important event in the career of a young scientist is the personal contact with great scientists. I was lucky to witness Hans Krebs from the closest quarters. There was no one quite like him.I am immensely grateful to the National Institutes of Health, the American Heart Association, and other funding agencies for >40 years of extramural support. Sometimes I feel that the field might be better served by building larger programs spanning a greater latitude and sometimes I feel that my own research projects have not fully exploited their translational potential; for instance, in reverse remodeling of the failing heart or in a targeted metabolic treatment of disordered cardiac function in extreme states of metabolic dysfunction, ranging from cachexia at one end of the spectrum to obesity at the other end.You asked for my advice to a young scientist. My answer is very simple. Know yourself, what you can do and what you cannot do. No scientist has ever been praised for the attempt to solve a difficult problem for which there are no adequate tools or talents to solve it. As Goethe said: “Stars you must not desire; stars you can only admire.” It is a challenge to make the best out of the present circumstances. That would be my advice for everyone. Know yourself and do not forget the people who matter most to you. The road to success is always under construction and seldom leads to financial reward.Do you have some final words to summarize your career?I am very proud of the work done by >50 students, residents, fellows, postdoctoral fellows, and research assistants in the lab. Many of my former trainees now run their own labs, whereas others have chosen rewarding clinical positions; taken together, their work under the big tent of metabolism has prepared them for their future careers.Before I embarked on my own academic work in Houston, I learned to serve and to think in a group of like-minded colleagues at the Boston City Hospital, to work at the bench and at the bedside at the Brigham, and to build my own tools to address the right questions for research in the Krebs lab in Oxford. All these lessons have put me through the roughest patches with my own work subsequently. Most of all, I learned to recognize that in research, as in the practice of medicine, we depend on each other in myriad ways. We are all in it together.Article InformationSources of FundingNone.Nonstandard Abbreviations and AcronymsFDGfluorodeoxyglucoseSGLT2sodium-glucose transport protein 2Disclosures None.FootnotesInquiries related to this profile, or the “Paths to Discovery” series, may be directed to the Editorial Office at [email protected]org.For Sources of Funding and Disclosures, see page 1663.Circulation is available at www.ahajournals.org/journal/circ