IN
MEMORIAM
A Tribute to Dr John H. Laragh Michael A. Weber, MD From the Downstate Medical Center, The State University of New York, Brooklyn, NY
sin system in mediating increases in blood pressure in response to renal ischemia. John then went a step further, questioning whether control of aldosterone, which recently had been demonstrated to have blood pressure–raising properties, might depend on the renin system. Thanks to the availability of angiotensin II, which had just been synthesized, he was able to undertake classic experiments in human volunteers in which he demonstrated that angiotensin II, in contrast to every other pressor hormone he tested, was able to stimulate the secretion of aldosterone. This demonstration that the renin-angiotensin system played a major role in regulating aldosterone’s release earned Dr Laragh the prestigious Stouffer Award of the Council for High Blood Pressure Research of the American Heart Association. In many respects, John Laragh was among the very first people to understand the mechanisms that underlie malignant or accelerated forms of hypertension.
A MAJOR BREAKTHROUGH
John Henry Laragh died on March 20, 2015. He was 90. John grew up in Yonkers, just outside New York City. He attended medical school at Cornell University and went on to do his residency work in medicine at the College of Physicians and Surgeons at Columbia University. He spent a considerable part of his early career at Columbia where eventually he became Chief of the Division of Nephrology. Early in his career, John Laragh became fascinated by hypertension, which, at the time, was focused mainly on patients with very high blood pressures. He observed that his patients with malignant hypertension had poor outcomes, whereas those with primary aldosteronism–– despite having blood pressures just as high––appeared to have a far better prognosis. John quickly realized the heterogeneous nature of hypertension and the fact that neuroendocrine factors as well as volume factors played key roles in this condition. Just a few years later, this understanding was to blossom into major scientific breakthroughs that changed the clinical practice of hypertension.
In 1972, John Laragh, aided by a talented group of younger colleagues working in his division, published a remarkable paper––truly a landmark publication––in The New England Journal of Medicine. Very simply, this article made the argument that hypertensive patients with high levels of plasma renin activity had an increased susceptibility to major vascular events. This finding was later confirmed by a larger study that again linked high renin levels to coronary events. John and his colleagues soon recognized that this finding went beyond the obvious physiologic relationship between the vasoconstrictor effects of the renin angiotensin system and blood pressure. Rather, they recognized that excess activity of the renin-angiotensin system, even independent of hypertension, might be a critical factor in causing vascular pathology and could therefore be a target for investigation in a whole array of cardiovascular conditions. Over the following 30 years, these speculations led to dramatic advances in the management of such conditions as heart failure, coronary disease, and chronic kidney disease.
INNOVATIVE CLINICAL SCIENCE
A SECOND BLOCKBUSTER STUDY
John Laragh had been strongly impressed by the seminal work of the surgeon, Harry Goldblatt, who had demonstrated the important role of the renin-angiotenAddress for correspondence: Michael A. Weber, MD, Downstate Medical Center, The State University of New York, New York, NY 11203 E-mail: [email protected] DOI: 10.1111/jch.12605
Just one year later, in 1973, John and his colleagues published a second dramatic publication, again in The New England Journal of Medicine. In this article, they reported that plasma renin activity was predictive of the blood pressure responses to drug therapy in patients with hypertension. In particular, patients with medium or high levels of renin responded particularly well to the renin-lowering effects of the newly available b-blocker, propranolol. Quite apart from the practical clinical The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
495
In Memoriam
implications of this discovery, it was now evident that far beyond its involvement in renovascular disease, renin was a central player in primary or essential hypertension. The whole landscape of this disease had changed. John Laragh and his team, including his wife, the scientist Dr Jean Sealey, went on to expand this concept and recognize that measurements of plasma renin activity could reveal a critical heterogeneity in clinical hypertension: Whereas patients with high renin activity would respond with large blood pressure reductions when given anti-renin agents, those whose renin levels were low––presumably because of the suppressive effects on renin of excess sodium and volume––would respond particularly well to diuretic agents. Thus was born the “vasoconstriction-volume hypothesis” of hypertension. In this construct, high renin levels were a marker for vasoconstriction-mediated hypertension, low renin levels were a marker for volumedependent hypertension, and medium or normal levels indicated that both mechanisms were at work and helped define patients who probably would require treatments targeted at both renin reduction and volume reduction. Awareness of these powerful discoveries was quickly recognized in the lay community, and in 1975 John Laragh was on the cover of Time magazine together with the arresting caption: “Hypertension: Conquering the Silent Killer.”
THE MOVE TO CORNELL In 1975, in the middle of these profound research breakthroughs, John Laragh accepted an offer to establish an interdisciplinary cardiovascular center at the Cornell University Medical Center. At Columbia, not bothering with any administrative formalities, John had boldly hung a Hypertension Center sign outside his clinical unit. But it was at Cornell that John could expand this idea into the innovative concept of a Hypertension Center that focused attention on this condition as a major clinical and research discipline. It is noteworthy that what at first seemed to be an unusual step has since been replicated in multiple institutions around the world. John’s discoveries clearly brought a whole new dimension to the study of hypertension, and soon after arriving at Cornell John was successful in obtaining a large program grant––a Specialized Center of Research Grant from the National Institutes of Health–– devoted to supporting integrated clinical and basic science explorations of the pathophysiology and treatment of hypertension. The Hypertension Center soon became a magnet for patients from all over the United States with difficult-tocontrol hypertension who had heard of the Center’s reputation for understanding and treating this tough condition. John’s magical ability to identify and attract young investigators around the world and add their talents to his ongoing work continued to be a major part of his commitment to expanding the understanding and care of hypertension. 496
The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
Within just 2 years of coming to Cornell, John became Chief of the Division of Cardiology as well. It is interesting to note that hypertension tends to intersect with three of the traditional medical disciplines: nephrology, cardiology, and endocrinology. John was an exceptional standard bearer for all three: he had led nephrology at Columbia; he now led Cardiology at Cornell; and his pivotal scientific work had been largely in the domain of endocrinology, particularly the mineralocorticoid and renin-angiotensin systems.
CONFRONTING THE NAYSAYERS In recounting John Laragh’s pivotal achievements it is impossible to overlook the responses that his remarkable breakthroughs evoked among his colleagues. In his lectures he would proudly claim, “Our publications are the most quoted in the field,” and then, after the briefest pause, add: “But only to disagree with them!” Simply put, there was a great deal of questioning, even to the point of hostility, regarding the claims that plasma renin activity was predictive of cardiovascular prognosis, and, equally, that measuring plasma renin activity could identify disparate forms of hypertension and so guide optimal therapy. Those of us who worked with John saw clearly the passion and commitment he brought to these scientific concepts. The renin story became a focal point of controversy at major scientific meetings around the world, often highlighted by debates between John Laragh and the skeptics. But even though the controversy became intense, in many ways it was highly productive. After all, it forced believers and nonbelievers into explaining the basic mechanisms of hypertension and the vascular disease that accompanies it. John Laragh was too busy to attend all the meetings to which he was invited to defend the renin thesis, so others of us in the Cornell group––after detailed and lengthy discussions with John––had the opportunity to speak for the team. Those were exciting days, for the lively and at times angry confrontations that arose from the renin story provided a great experience for those of us destined to remain in academic medicine. One of the big issues with studying renin was that there was no universal method for measuring it, so often the critics of the new concepts simply did not have the resources to adequately study this complex area. I came to realize the importance of meticulous methodology, for the renin assay perfected by Jean Sealey provided a sensitivity that allowed us to discriminate the different renin subgroups more reliably than with previous methods. In fact, Jean’s protocol required a longer than standard incubation period for the renin activity assay, thus providing confidence that we could accurately identify patients with low renin hypertension in whom renin played little or no role in sustaining their hypertension. As well, Jean had already discovered that storing plasma samples cold but not frozen could lead to inaccuracies because this allowed the cryoactivation of pro-renin to renin, thus causing patients with low renin to be misclassified as having medium renin.
In Memoriam
In fact, Jean’s work with pro-renin was to become one of the signal contributions of the Laragh team to the science of the renin-angiotensin system in reproductive physiology. The other important issue when considering plasma renin measurements was the fact that physiologically they are affected by sodium balance, so that our use of a reninsodium nomogram to classify patients into low, normal, or high renin subgroups added further exactness to the process. Eventually, of course, the thinking behind the renin thesis became more broadly accepted, and for John Laragh and his colleagues it became a measure of satisfaction to see how other workers in the field were starting to write routinely about “high renin” and “low renin” hypertension, confirming the growing acceptance of these concepts.
THE NEXT STEPS
The b-blockers were useful tools for studying the relationship between renin and hypertension because they decreased renin release from the kidney and so inhibited the renin-angiotensin system. But John Laragh and his colleagues had far more selective and powerful approaches in mind, and started to undertake clinical investigation with saralasin, a powerful parenteral nonselective angiotensin II receptor antagonist. Unfortunately, this compound was a partial agonist and reduced blood pressure only in patients with high renin levels. However, Dr Laragh was able to get access to teprotide, an investigational rapidly acting inhibitor of the angiotensin-converting enzyme extracted from the venom of the Brazilian pit viper. This agent lowered blood pressure in both patients with high and normal renin and allowed more precise estimates of the role of the renin-angiotensin system in maintaining hypertension. Although we were able to learn a great deal about hypertension from this work, the fact that saralasin and teprotide could be given only by intravenous infusion, while making them great investigational tools, meant that they could not be used routinely as clinical therapies. For this reason, the development of the oral angiotensin-converting enzyme inhibitors became an important priority, and for John Laragh a powerfully pursued mission. He knew that scientists at the pharmaceutical company, Squibb (later, Bristol-Myers Squibb), were working with captopril, the first orally effective drug of this class. John approached the Squibb team with the powerful message that this new type of therapy could be revolutionary for the management of hypertension and, beyond that, for a variety of cardiovascular conditions. John expended a great deal of energy in bringing this about; and soon afterwards, I also found myself in support of his mission, talking to major financial organizations to persuade them that this new pharmacology would have a major influence on the practice of cardiovascular medicine and that their investments in the company would be well rewarded. Those were fascinating times––with truly broadening experiences for young academicians––and ultimately these efforts
served to support the translation of John Laragh’s scientific concept into clinical reality.
A CONTINUING BATTLE It is interesting, looking back over time, to recognize how slowly these vital discoveries actually penetrated into clinical practice. In fact, 20 years after the first critical publications regarding the role of the reninangiotensin system in mediating hypertension and affecting cardiovascular prognosis, the publication of the Fifth Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC V) in 1993 still advocated that diuretics––which Dr Laragh and colleagues had shown were treatments of choice mainly for patients with low-renin hypertension––be used as first-line treatment for all hypertension. It was as though John Laragh’s research, not to mention the work of large numbers of investigators around the world, had simply not taken place! John and I wrote the editorial that accompanied the publication of this JNC report, which we titled “Steps Forward and Steps Backward,” in which we argued strongly that the report’s therapeutic recommendations were not in the best interests of many patients. In fact, John never stopped fighting to establish the construct of hypertension that he had done so much to create, and in 2002 he published his book: Laragh’s Lessons in Renin System Pathophysiology for Treating Hypertension and Its Fatal Cardiovascular Consequences. It is remarkable how John had maintained his unflagging energy for 30 years beyond the original publications. It is a tribute to the persistence of John and like-minded colleagues that the therapies that Laragh helped create became and still remain the most widely used agents for hypertension and other cardiovascular and renal conditions. (For readers interested in reading the pivotal scientific publications of John Laragh, Jean Sealey, and their colleagues, I recommend the citations given in Sealey JE. Am J Hypertens. 2013;27:1019–1023 and Weber MA. Am J Hypertens. 2013;27:1008–1009).
PROFESSIONAL ACTIVITIES Although John Laragh made contributions to many professional organizations, he will probably be best remembered as a founder of the American Society of Hypertension (ASH) and for serving as its first president. Watching John in action was highly instructive, for he approached this task with considerable planning. He recognized that a new society in a discipline such as hypertension could function only if it had adequate external support. We spent considerable efforts in approaching industry sources to become corporate members of ASH and provide the resources needed to make the society a viable year-round entity with a strong infrastructure. His choice of the early members of the Society’s board again reflected his thoughtfulness, as he included leaders from the domains of cardiology, nephrology, and endocrinology, as well as leading hypertension names. The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
497
In Memoriam
The Society was to grow in importance and influence, a testimony to John’s skill and vision. John also became the first Editor-in-Chief of The American Journal of Hypertension, and once again those of us working with him on this project learned the importance of finding the right publisher, setting up the right scientific model for the Journal, and ensuring that influential people in the field would contribute their best work. Just as there had been a negative reaction to John Laragh’s early advocacy of the renin theory, we now also encountered some resistance from colleagues who felt that a new society and new journal were not fully justified in the hypertension arena. But once again, over time, these entities have become well established. John’s reputation was not just confined to the United States, but was recognized around the world. He served a term as president of the International Society of Hypertension, contributing again to an organization committed to the underlying science of hypertension.
THE PERSONAL SIDE Knowing that I had worked with him, people would ask, “What is John Laragh really like?” There was an expectation that John’s larger-than-life reputation was based to some extent on an extroverted or even flamboyant style. But this was not the case at all. In many ways John Laragh was a quiet, even withdrawn, man whose large public persona derived from the fierce advocacy of his scientific beliefs. Despite his success in making his ideas so well-known, I suspected that John, as a person, did not always relish the spotlight. But, at the same time, Dr Laragh was a demanding person to work with. He and Jean were both focused on getting the details right, which of course is the hallmark of successful research. This was exemplified in writing manuscripts. We would meet day after day to work as a group on major papers––a process John referred to as “Bible reading.” Every word had to perform its precise job, every sentence had to explain a concept with clarity and without ambiguity. Similarly, John read the work of others with great intensity, carefully examining every part of the science, interpreting what might be hidden in the nuances. When I worked with John––and for quite some time after I set up my own activities in California––he would get in touch to exchange thoughts on newly published papers in our field.
498
The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
John was a man with broad interests. He was an engaging companion, shared his wide repertoire of jokes––some of them rather edgy––and was altogether a good and loyal friend. He was very much attached to his family, and for all the years that I knew him, Jean and he were a devoted couple. Jean had a long history of working in John’s laboratory. After they were married in 1974 she progressively took a leading role in his work and writing. John and Jean’s son, Robert, and his wife, Marci, were able to provide them with the delight of a granddaughter, Eliana. At heart, John was a rebel, and recognized that quality in others. I recall how in 1992, as the presidential election loomed, John appeared one day with a large Ross Perot button on his lapel. I was never certain that John was really on board with the philosophy of this independent candidate, but he couldn’t resist supporting a maverick attempting to overcome insurmountable odds. John was passionate about golf. Anyone who visited his office couldn’t fail to notice a photograph of him next to the great professional golfer, Jack Nicklaus, presumably as the two of them were in the middle of a round of golf. John and Jean shared a love of golf and took pleasure in inviting guests to their summer home adjacent to Shinnecock Hills, the renowned golf course on New York’s Long Island. As John started to contemplate a less busy professional life, he and Jean moved to the Village of Golf in Florida. This is a beautiful setting for avid golfers, and I had the opportunity of asking John, after living there for a few months, how he was enjoying a life built around golf. He answered very positively, yet at the same time I had little doubt that in John’s heart of hearts his greatest passion still lay in the field of science he had helped create, and that even at this point of his life he still devoted a large part of his intellectual and emotional energy to advancing his ideas. John’s career represented an enormous contribution. Many millions of people in the United States and around the world have been protected from strokes and heart disease, and have had their lives significantly lengthened, because of John Laragh’s creative research and teaching. In recent years, as John thought back on his life and career, I would like to think that the profound satisfaction merited by these remarkable accomplishments were a source of warmth and strength for this most distinguished man.
MEMORIAM
A Tribute to Dr John H. Laragh Michael A. Weber, MD From the Downstate Medical Center, The State University of New York, Brooklyn, NY
sin system in mediating increases in blood pressure in response to renal ischemia. John then went a step further, questioning whether control of aldosterone, which recently had been demonstrated to have blood pressure–raising properties, might depend on the renin system. Thanks to the availability of angiotensin II, which had just been synthesized, he was able to undertake classic experiments in human volunteers in which he demonstrated that angiotensin II, in contrast to every other pressor hormone he tested, was able to stimulate the secretion of aldosterone. This demonstration that the renin-angiotensin system played a major role in regulating aldosterone’s release earned Dr Laragh the prestigious Stouffer Award of the Council for High Blood Pressure Research of the American Heart Association. In many respects, John Laragh was among the very first people to understand the mechanisms that underlie malignant or accelerated forms of hypertension.
A MAJOR BREAKTHROUGH
John Henry Laragh died on March 20, 2015. He was 90. John grew up in Yonkers, just outside New York City. He attended medical school at Cornell University and went on to do his residency work in medicine at the College of Physicians and Surgeons at Columbia University. He spent a considerable part of his early career at Columbia where eventually he became Chief of the Division of Nephrology. Early in his career, John Laragh became fascinated by hypertension, which, at the time, was focused mainly on patients with very high blood pressures. He observed that his patients with malignant hypertension had poor outcomes, whereas those with primary aldosteronism–– despite having blood pressures just as high––appeared to have a far better prognosis. John quickly realized the heterogeneous nature of hypertension and the fact that neuroendocrine factors as well as volume factors played key roles in this condition. Just a few years later, this understanding was to blossom into major scientific breakthroughs that changed the clinical practice of hypertension.
In 1972, John Laragh, aided by a talented group of younger colleagues working in his division, published a remarkable paper––truly a landmark publication––in The New England Journal of Medicine. Very simply, this article made the argument that hypertensive patients with high levels of plasma renin activity had an increased susceptibility to major vascular events. This finding was later confirmed by a larger study that again linked high renin levels to coronary events. John and his colleagues soon recognized that this finding went beyond the obvious physiologic relationship between the vasoconstrictor effects of the renin angiotensin system and blood pressure. Rather, they recognized that excess activity of the renin-angiotensin system, even independent of hypertension, might be a critical factor in causing vascular pathology and could therefore be a target for investigation in a whole array of cardiovascular conditions. Over the following 30 years, these speculations led to dramatic advances in the management of such conditions as heart failure, coronary disease, and chronic kidney disease.
INNOVATIVE CLINICAL SCIENCE
A SECOND BLOCKBUSTER STUDY
John Laragh had been strongly impressed by the seminal work of the surgeon, Harry Goldblatt, who had demonstrated the important role of the renin-angiotenAddress for correspondence: Michael A. Weber, MD, Downstate Medical Center, The State University of New York, New York, NY 11203 E-mail: [email protected] DOI: 10.1111/jch.12605
Just one year later, in 1973, John and his colleagues published a second dramatic publication, again in The New England Journal of Medicine. In this article, they reported that plasma renin activity was predictive of the blood pressure responses to drug therapy in patients with hypertension. In particular, patients with medium or high levels of renin responded particularly well to the renin-lowering effects of the newly available b-blocker, propranolol. Quite apart from the practical clinical The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
495
In Memoriam
implications of this discovery, it was now evident that far beyond its involvement in renovascular disease, renin was a central player in primary or essential hypertension. The whole landscape of this disease had changed. John Laragh and his team, including his wife, the scientist Dr Jean Sealey, went on to expand this concept and recognize that measurements of plasma renin activity could reveal a critical heterogeneity in clinical hypertension: Whereas patients with high renin activity would respond with large blood pressure reductions when given anti-renin agents, those whose renin levels were low––presumably because of the suppressive effects on renin of excess sodium and volume––would respond particularly well to diuretic agents. Thus was born the “vasoconstriction-volume hypothesis” of hypertension. In this construct, high renin levels were a marker for vasoconstriction-mediated hypertension, low renin levels were a marker for volumedependent hypertension, and medium or normal levels indicated that both mechanisms were at work and helped define patients who probably would require treatments targeted at both renin reduction and volume reduction. Awareness of these powerful discoveries was quickly recognized in the lay community, and in 1975 John Laragh was on the cover of Time magazine together with the arresting caption: “Hypertension: Conquering the Silent Killer.”
THE MOVE TO CORNELL In 1975, in the middle of these profound research breakthroughs, John Laragh accepted an offer to establish an interdisciplinary cardiovascular center at the Cornell University Medical Center. At Columbia, not bothering with any administrative formalities, John had boldly hung a Hypertension Center sign outside his clinical unit. But it was at Cornell that John could expand this idea into the innovative concept of a Hypertension Center that focused attention on this condition as a major clinical and research discipline. It is noteworthy that what at first seemed to be an unusual step has since been replicated in multiple institutions around the world. John’s discoveries clearly brought a whole new dimension to the study of hypertension, and soon after arriving at Cornell John was successful in obtaining a large program grant––a Specialized Center of Research Grant from the National Institutes of Health–– devoted to supporting integrated clinical and basic science explorations of the pathophysiology and treatment of hypertension. The Hypertension Center soon became a magnet for patients from all over the United States with difficult-tocontrol hypertension who had heard of the Center’s reputation for understanding and treating this tough condition. John’s magical ability to identify and attract young investigators around the world and add their talents to his ongoing work continued to be a major part of his commitment to expanding the understanding and care of hypertension. 496
The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
Within just 2 years of coming to Cornell, John became Chief of the Division of Cardiology as well. It is interesting to note that hypertension tends to intersect with three of the traditional medical disciplines: nephrology, cardiology, and endocrinology. John was an exceptional standard bearer for all three: he had led nephrology at Columbia; he now led Cardiology at Cornell; and his pivotal scientific work had been largely in the domain of endocrinology, particularly the mineralocorticoid and renin-angiotensin systems.
CONFRONTING THE NAYSAYERS In recounting John Laragh’s pivotal achievements it is impossible to overlook the responses that his remarkable breakthroughs evoked among his colleagues. In his lectures he would proudly claim, “Our publications are the most quoted in the field,” and then, after the briefest pause, add: “But only to disagree with them!” Simply put, there was a great deal of questioning, even to the point of hostility, regarding the claims that plasma renin activity was predictive of cardiovascular prognosis, and, equally, that measuring plasma renin activity could identify disparate forms of hypertension and so guide optimal therapy. Those of us who worked with John saw clearly the passion and commitment he brought to these scientific concepts. The renin story became a focal point of controversy at major scientific meetings around the world, often highlighted by debates between John Laragh and the skeptics. But even though the controversy became intense, in many ways it was highly productive. After all, it forced believers and nonbelievers into explaining the basic mechanisms of hypertension and the vascular disease that accompanies it. John Laragh was too busy to attend all the meetings to which he was invited to defend the renin thesis, so others of us in the Cornell group––after detailed and lengthy discussions with John––had the opportunity to speak for the team. Those were exciting days, for the lively and at times angry confrontations that arose from the renin story provided a great experience for those of us destined to remain in academic medicine. One of the big issues with studying renin was that there was no universal method for measuring it, so often the critics of the new concepts simply did not have the resources to adequately study this complex area. I came to realize the importance of meticulous methodology, for the renin assay perfected by Jean Sealey provided a sensitivity that allowed us to discriminate the different renin subgroups more reliably than with previous methods. In fact, Jean’s protocol required a longer than standard incubation period for the renin activity assay, thus providing confidence that we could accurately identify patients with low renin hypertension in whom renin played little or no role in sustaining their hypertension. As well, Jean had already discovered that storing plasma samples cold but not frozen could lead to inaccuracies because this allowed the cryoactivation of pro-renin to renin, thus causing patients with low renin to be misclassified as having medium renin.
In Memoriam
In fact, Jean’s work with pro-renin was to become one of the signal contributions of the Laragh team to the science of the renin-angiotensin system in reproductive physiology. The other important issue when considering plasma renin measurements was the fact that physiologically they are affected by sodium balance, so that our use of a reninsodium nomogram to classify patients into low, normal, or high renin subgroups added further exactness to the process. Eventually, of course, the thinking behind the renin thesis became more broadly accepted, and for John Laragh and his colleagues it became a measure of satisfaction to see how other workers in the field were starting to write routinely about “high renin” and “low renin” hypertension, confirming the growing acceptance of these concepts.
THE NEXT STEPS
The b-blockers were useful tools for studying the relationship between renin and hypertension because they decreased renin release from the kidney and so inhibited the renin-angiotensin system. But John Laragh and his colleagues had far more selective and powerful approaches in mind, and started to undertake clinical investigation with saralasin, a powerful parenteral nonselective angiotensin II receptor antagonist. Unfortunately, this compound was a partial agonist and reduced blood pressure only in patients with high renin levels. However, Dr Laragh was able to get access to teprotide, an investigational rapidly acting inhibitor of the angiotensin-converting enzyme extracted from the venom of the Brazilian pit viper. This agent lowered blood pressure in both patients with high and normal renin and allowed more precise estimates of the role of the renin-angiotensin system in maintaining hypertension. Although we were able to learn a great deal about hypertension from this work, the fact that saralasin and teprotide could be given only by intravenous infusion, while making them great investigational tools, meant that they could not be used routinely as clinical therapies. For this reason, the development of the oral angiotensin-converting enzyme inhibitors became an important priority, and for John Laragh a powerfully pursued mission. He knew that scientists at the pharmaceutical company, Squibb (later, Bristol-Myers Squibb), were working with captopril, the first orally effective drug of this class. John approached the Squibb team with the powerful message that this new type of therapy could be revolutionary for the management of hypertension and, beyond that, for a variety of cardiovascular conditions. John expended a great deal of energy in bringing this about; and soon afterwards, I also found myself in support of his mission, talking to major financial organizations to persuade them that this new pharmacology would have a major influence on the practice of cardiovascular medicine and that their investments in the company would be well rewarded. Those were fascinating times––with truly broadening experiences for young academicians––and ultimately these efforts
served to support the translation of John Laragh’s scientific concept into clinical reality.
A CONTINUING BATTLE It is interesting, looking back over time, to recognize how slowly these vital discoveries actually penetrated into clinical practice. In fact, 20 years after the first critical publications regarding the role of the reninangiotensin system in mediating hypertension and affecting cardiovascular prognosis, the publication of the Fifth Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC V) in 1993 still advocated that diuretics––which Dr Laragh and colleagues had shown were treatments of choice mainly for patients with low-renin hypertension––be used as first-line treatment for all hypertension. It was as though John Laragh’s research, not to mention the work of large numbers of investigators around the world, had simply not taken place! John and I wrote the editorial that accompanied the publication of this JNC report, which we titled “Steps Forward and Steps Backward,” in which we argued strongly that the report’s therapeutic recommendations were not in the best interests of many patients. In fact, John never stopped fighting to establish the construct of hypertension that he had done so much to create, and in 2002 he published his book: Laragh’s Lessons in Renin System Pathophysiology for Treating Hypertension and Its Fatal Cardiovascular Consequences. It is remarkable how John had maintained his unflagging energy for 30 years beyond the original publications. It is a tribute to the persistence of John and like-minded colleagues that the therapies that Laragh helped create became and still remain the most widely used agents for hypertension and other cardiovascular and renal conditions. (For readers interested in reading the pivotal scientific publications of John Laragh, Jean Sealey, and their colleagues, I recommend the citations given in Sealey JE. Am J Hypertens. 2013;27:1019–1023 and Weber MA. Am J Hypertens. 2013;27:1008–1009).
PROFESSIONAL ACTIVITIES Although John Laragh made contributions to many professional organizations, he will probably be best remembered as a founder of the American Society of Hypertension (ASH) and for serving as its first president. Watching John in action was highly instructive, for he approached this task with considerable planning. He recognized that a new society in a discipline such as hypertension could function only if it had adequate external support. We spent considerable efforts in approaching industry sources to become corporate members of ASH and provide the resources needed to make the society a viable year-round entity with a strong infrastructure. His choice of the early members of the Society’s board again reflected his thoughtfulness, as he included leaders from the domains of cardiology, nephrology, and endocrinology, as well as leading hypertension names. The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
497
In Memoriam
The Society was to grow in importance and influence, a testimony to John’s skill and vision. John also became the first Editor-in-Chief of The American Journal of Hypertension, and once again those of us working with him on this project learned the importance of finding the right publisher, setting up the right scientific model for the Journal, and ensuring that influential people in the field would contribute their best work. Just as there had been a negative reaction to John Laragh’s early advocacy of the renin theory, we now also encountered some resistance from colleagues who felt that a new society and new journal were not fully justified in the hypertension arena. But once again, over time, these entities have become well established. John’s reputation was not just confined to the United States, but was recognized around the world. He served a term as president of the International Society of Hypertension, contributing again to an organization committed to the underlying science of hypertension.
THE PERSONAL SIDE Knowing that I had worked with him, people would ask, “What is John Laragh really like?” There was an expectation that John’s larger-than-life reputation was based to some extent on an extroverted or even flamboyant style. But this was not the case at all. In many ways John Laragh was a quiet, even withdrawn, man whose large public persona derived from the fierce advocacy of his scientific beliefs. Despite his success in making his ideas so well-known, I suspected that John, as a person, did not always relish the spotlight. But, at the same time, Dr Laragh was a demanding person to work with. He and Jean were both focused on getting the details right, which of course is the hallmark of successful research. This was exemplified in writing manuscripts. We would meet day after day to work as a group on major papers––a process John referred to as “Bible reading.” Every word had to perform its precise job, every sentence had to explain a concept with clarity and without ambiguity. Similarly, John read the work of others with great intensity, carefully examining every part of the science, interpreting what might be hidden in the nuances. When I worked with John––and for quite some time after I set up my own activities in California––he would get in touch to exchange thoughts on newly published papers in our field.
498
The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
John was a man with broad interests. He was an engaging companion, shared his wide repertoire of jokes––some of them rather edgy––and was altogether a good and loyal friend. He was very much attached to his family, and for all the years that I knew him, Jean and he were a devoted couple. Jean had a long history of working in John’s laboratory. After they were married in 1974 she progressively took a leading role in his work and writing. John and Jean’s son, Robert, and his wife, Marci, were able to provide them with the delight of a granddaughter, Eliana. At heart, John was a rebel, and recognized that quality in others. I recall how in 1992, as the presidential election loomed, John appeared one day with a large Ross Perot button on his lapel. I was never certain that John was really on board with the philosophy of this independent candidate, but he couldn’t resist supporting a maverick attempting to overcome insurmountable odds. John was passionate about golf. Anyone who visited his office couldn’t fail to notice a photograph of him next to the great professional golfer, Jack Nicklaus, presumably as the two of them were in the middle of a round of golf. John and Jean shared a love of golf and took pleasure in inviting guests to their summer home adjacent to Shinnecock Hills, the renowned golf course on New York’s Long Island. As John started to contemplate a less busy professional life, he and Jean moved to the Village of Golf in Florida. This is a beautiful setting for avid golfers, and I had the opportunity of asking John, after living there for a few months, how he was enjoying a life built around golf. He answered very positively, yet at the same time I had little doubt that in John’s heart of hearts his greatest passion still lay in the field of science he had helped create, and that even at this point of his life he still devoted a large part of his intellectual and emotional energy to advancing his ideas. John’s career represented an enormous contribution. Many millions of people in the United States and around the world have been protected from strokes and heart disease, and have had their lives significantly lengthened, because of John Laragh’s creative research and teaching. In recent years, as John thought back on his life and career, I would like to think that the profound satisfaction merited by these remarkable accomplishments were a source of warmth and strength for this most distinguished man.
