Mentors, role models, and matters of the heart

William Harvey 

It is unnecessary for me to reiterate William Harvey’s classic description (Figure 1) of the continuous flow of blood from the heart, through the larger and smaller arteries, to the venous limb of the circulation, and back to the heart. This obvious circuit to you was clearly recited to me 2 years ago by my 3-year-old grandson, but let us remember that it took ages to culminate in William Harvey’s elucidation of his concept in his Execitatio Anatomica de Motu Cordis et Sanguinis in Animalibus, 1616 and 1628. Not only did his rather short 72 pages and 1 figure discourse startle the medical “thought leaders” (as we hear this term today), but it actually left a major gap for a complete understanding of the entire circuitry of blood. Harvey did not include in his well-reasoned thinking the existence of capillaries and the critical means whereby the blood passes from the arterial to the venous limbs of the circulation.

View Large Image Download to PowerPoint

Figure 1. William Harvey, 1578–1657 (left) and Hieronymus Fabricius (ab Aquapendente), 1537–1619 (right).

So much for Harvey’s significant finding — but who in his early experiences in medicine could have stimulated him to think critically about the anatomy of the circulation? There is little that I could draw from in my brief review of this subject, but, like all mentors, I went to my nearest source of medical historical information, my friend, former mentee, and serious student of medical history, Hector O. Ventura, MD. While he did not provide me with a definitive answer, he did say that Harvey entered Caius College, Cambridge at the age of 16 years. After his collegiate schooling at Caius College, Harvey went on to Padua probably at the suggestion of its Master John Caius who, earlier, was a student of Andreas Vasalius, the father of modern anatomy. Harvey studied medicine in Padua under the mentorship of the famous anatomist Hieronymus Fabricius (ab Aquapendente) (Figure 1) who was the first to demonstrate valves in veins (De Venarum Osliolis, 1603). Hector was not aware of any specific discussions between Harvey and his mentor Fabricius concerning the circulation, but it is highly probable that he was impressed by his master’s drawings of heart, aorta, and vessels to be so stimulated. No doubt it was his mentor Fabricius who gave Harvey this impetus and the necessity of veins to assure the venous return of blood to the heart. In support of this inference, late in his life Harvey confided to Robert Boyle that it was his realizations about veins and the one-way flow of blood that led him to his concept of the circulation of blood. I must add parenthetically, however, that some of Harvey’s contemporaneous colleagues (including William Heberden) were not nearly as impressed with his contribution as we are today.

Mentors and Role Models 

In my early medical school training, I have much appreciation to express to John C. Krantz, PhD, my Professor of Pharmacology, and to Theodore E. Woodward, MD, my Professor of Medicine. Dr. Krantz steered me to Robert P. Grant, MD, at the then National Heart Institute after my sophomore year as a Public Health Service fellow. During my two summer fellowships at the National Institutes of Health (NIH), Bob Grant stimulated my interest in the heart and introduced me to Dr. W. Proctor Harvey at Georgetown University where I subsequently trained. I have so very much to thank each of these major academicians who kept my thinking focused: Bob, at the National Heart Institute, where he subsequently became its Director1; Krantz, through his personal interest in me and our rewarding and memorable discussions while in medical school; and Ted Woodward who provided me with Departmental NIH funds to work on my first clinical project and who continued to stimulate my interests in our frequent meetings for over 50 years. It was my relationship with “Proc” Harvey that prompted my training at Georgetown and my later thinking underlying my first clinical investigations on the heart in hypertension.

It was these four role models, and a fifth, Hugh H. Hussey, MD, Chairman of the Department of Medicine and Dean at Georgetown, who gently and subtly, but effectively, encouraged my academic pursuits throughout my training and, on my recollections, even to recent years. Hugh Hussey died all too prematurely following his Editorship of the Journal of the American Medical Association, and I am consciously aware even today for his enormous encouragement who instilled in me the necessity to communicate medical knowledge and for many other more personal thoughts. More about Proctor Harvey to come.

Edward D. Freis 

Edward D. Freis, MD, began and stimulated my life’s commitment to the field of hypertension2 (Figure 2). Ed inculcated in me my preoccupation with the hemodynamics of hypertension, the role of the heart, the importance of the various organ circulations, the role of the veins in hypertension, and, of course, during this new era of antihypertensive therapy, with the hemodynamic and clinical assessment of drug treatment. During my fellowship years with Ed, I was honored when he invited me to comment on the drafts of his now classic paper “Hemodynamics of Hypertension,” which was invited by Drs. Irvine H. Page and Arthur C. Corcoran for Physiological Reviews.3 I still ask each of my research fellows and associates to read this paper carefully, and I continue to learn much from his remarkable contribution.

View Large Image Download to PowerPoint

Figure 2. Edward D. Freis, MD, 1926–2005.

Also, during these years Ed shared with me his many thoughts about the formulation of his totally original proposal (which had been just approved) to establish the first placebo-controlled, multicenter cardiovascular drug trial in medical history, the Veterans Administration Cooperative Study, which has since become a landmark in medical history. I was pleased and privileged to participate in this remarkable study as his research fellow in Washington, DC and, later, as a VA Clinical Investigator and faculty member at the Chicago (Northwestern University) and Oklahoma City (University of Oklahoma) Veterans Administration Hospitals.

With the carefully detailed, but disciplined, approach I learned from Ed Freis in our hemodynamic studies and the lessons I gleaned much from “Proc” Harvey and his thinking on the mechanisms of the fourth heart sound and the role of the less compliant left ventricle in disease, I initiated my first series of hemodynamic studies with Irvine H. Page, MD, Harriet P. Dustan, MD, and Robert C. Tarazi, MD, at the Research Division of the Cleveland Clinic.

Bob Tarazi, my first research fellow in Cleveland, was immediately captured by Freis’ concept of “cardiogenic hypertension”3 and the role of the fourth heart sound and the left atrial abnormality (LAAb)4, 5, 6 in the development of hypertensive heart disease. We postulated that this abnormality provided the first clinical evidence of hypertensive heart disease — even before left ventricular hypertrophy (LVH) could be detected electrocardiographically (this was before the era of echocardiography).6 These studies demonstrated that LAAb was frequently associated with cardiac arrhythmias and the later appearance of atrial fibrillation, a finding which is only now being fully appreciated. In addition, left ventricular ejection rate was diminished and its tension time index and pressure time per beat were increased. Later, Francis G. Dunn, MD, my mentee and close friend from Glasgow, Scotland added this latter aspect of echocardiography to update our classification of hypertensive heart disease.7 In that first echocardiographic study of the heart in hypertension, we demonstrated that the left atrium (with LAAb) was indeed enlarged and was also associated with an increased left ventricular mass with increased posterior and septal wall thicknesses. And this was associated with impaired left ventricular ejection fraction and fiber shortening rate.7

Irvine H. Page and Harriet P. Dustan 

If there were any major lessons that I learned from these two remarkably rare role models, Irvine H. Page, MD and Harriet P. Dustan, MD (Figure 3), it was how to write a scientific paper, to think critically, and to appreciate the vital value of fundamental research and clinical investigation in medical practice. Most people consider Page’s Mosaic Theory of Hypertension a simplistic diagram.8 However, it is a very thoughtful and meaningful means to express mathematically, yet simplistically, the concept of multifactorial causation of disease. It may be used for many other complex problems be they economic, social, or scientific. Perhaps I use this diagrammatic technique too frequently, but I employ it primarily to honor Irv Page, a true giant in medical history. Not only should he be credited for this concept but, even more importantly, for his discoveries and synthesis of angiotensin II and serotonin, as well as for advocating and stimulating the establishment of the Institute of Medicine of the National Academy of Sciences.

View Large Image Download to PowerPoint

Figure 3. Irvine H. Page, MD, 1901–1991 (right) and Harriet P. Dustan, MD, 1920–1999 (left).

But it was Dusty who was my greatest scientific critic, a personal manuscript reviewer, a constant confidant, and one of Sherry and my best friends in our life. If there is one moving phrase that she reiterated to me for over 30 years, it was that our work together was her “halcyon days.” Together, we carefully studied our patients with hypertensive heart disease,4, 5, 6 the hyperdynamic beta-adrenergic circulatory state,9 and the relationship between hemodynamics, intravascular volume, and plasma renin activity.10 These two remarkable figures (and Ed Freis) were, without any doubt, my major role models in my academic career and truly dear personal friends.

My Esteemed Mentees 

Yes, Marc A. Pfeffer, MD, PhD and Janice M. Pfeffer, PhD (Figure 4), and I accomplished much together over the 7 years during which we were in Oklahoma. We demonstrated and confirmed the natural history of hypertensive heart disease in the best genetic model of essential hypertension, the spontaneously hypertensive rat (SHR)11; and we assessed the functional development of the hypertrophied left ventricle and its pumping ability.12, 13, 14, 15 Marc reviewed these findings and his subsequent contributions for this Society in his Harvey Lecture; I shall not presume to improve on them.

View Large Image Download to PowerPoint

Figure 4. Janice M. Pfeffer, PhD, 1943–2000 (left) and Marc A. Pfeffer, MD, PhD (right).

I will add to these findings, however, my current thinking about LVH: that we should no longer consider LVH as a primary risk factor, per se. Myocytic hypertrophy in the left ventricular chamber provides the physiological adaptation to a chronic pressure overload in order to prevent cardiac failure. Thus, after many years of thinking, working, and constant preoccupation on the subject of LVH, the actual risk of this factor, to my current way of thinking, resides basically in the epiphenomena of LVH: ischemia, fibrosis, apoptosis, inflammatory factors, chronic salt excess, and most likely other factors yet to be elucidated.16

Additionally, we have also learned much that end-stage renal disease in hypertension not only results from the elevated arterial pressure but, more importantly, is associated with afferent and efferent glomerular arteriolar constriction, ischemia, ultra-filtration, and hyaline deposition that promotes the glomerular and arteriolar injury.17, 18 We have demonstrated these changes developmentally with aging (and without any other intervention) in the SHR. In addition, we have shown repeatedly that the development of these renal hemodynamic alterations in nephrosclerosis can be produced in younger adult SHRs by inhibiting nitric oxide production. Moreover, these changes are closely related to the progressive development of hyperuricemia,19 not only in hypertension but also in atherosclerotic cardiovascular diseases.20 And we have also learned that the target-organ involvement of the heart and kidneys is not only preventable but also reversible.21

But what I experienced most from the Pfeffers and the over 125 research fellows in my experiences was the very special relationship that can exist between a mentor and mentee. I have editorialized on this subject earlier,22 and it goes down to this. A mentor is not an individual who works with a student for an hour or 2 weeks over a proscribed finite time interval (whether for a year or even 4 years). The mentor is a person who assumes the responsibility to work closely with his/her student not only through a specific period of training, but over a lifetime. Scarcely a week passes that I do not hear from Marc Pfeffer of see Hector Ventura, but I also try to maintain a close relationship with each of those many research fellows with whom we have learned together over the past 45 or more years. I still receive communications from Ed Freis’ children and his companion and from Irv Page’s son, and I also try to maintain communication with my “fellows” whether they are in Europe, South America, Japan, China, or the United States. I was truly overwhelmed 2 years ago when my Japanese academician colleagues related so very touchingly with me during our 3-month “exile” from New Orleans following Hurricanes Katrina and Rita and the ensuing flooding. Yes, I truly value this experience demonstrated by the Greek mentor long ago with Odysseus’ son Telamachus. Mentor has indeed provided a historical role model to me.

My Colleagues at Ochsner and Elsewhere 

Over the years, I have learned much from my colleague Richard N. Re, MD, and from my many other research associates and research fellows. I am also indebted to my institution, the Ochsner Clinic Foundation, for providing me with 31 years of ambiance to pursue my academic work. Almost all of my research fellows who were not American have returned to their home countries and academia; to list them all and to describe our many relationships would slight far too many wonderful people. I do want to express my appreciation, however, to several who have worked with me in our very recent studies dealing with the enigma of salt in hypertension, Doctors Dinko Susic, Jasmina Varagic, Xiaoyan Zhou, Michel Slama, and others.23, 24, 25, 26, 27 I have been tremendously impressed that, despite the very strong, yet complicated, relationship that exists between salt excess and hypertension, the demonstration of “salt sensitivity” has been exceedingly difficult to establish in a single patient were the response of arterial pressure the only factor. Clearly, to me, the problem is not solely related to a rise in arterial pressure coincident with salt-loading. The answer to this conundrum, at least in a major part, exists in one’s consideration of hypertension as a disease entity. To me, this does not simply mean the elevation of arterial pressure with a salt challenge, but to the myriad effects of salt on the target organs of the disease.28

“A Matter of the Heart” 

And, now, to return to the “matter of the heart.” As I stated earlier, none of my experiences in academic medicine would have been possible without the love and support of my wife Sherry. In our earlier years, as with many of you with your spouses or partners, Sherry provided the major input into our decision making. As our children grew and developed, she provided the role model, not only to them, but to me as well. In more recent years, as we were confronted by Mother Nature’s fury, she provided me with stability, encouragement, and the necessary roles and energy of my lifetime coworker. Perhaps, in totality, she has been my major Mentor, Role Model, and, of course, the “Matter of My Heart.”

Conclusion 

All of the foregoing is not unique to my personal experiences. My message, I am sure, is clear to each of you in medical academia and, more broadly, to all whose personal lifetime accomplishments merit significance. The impact that a person makes on one’s profession (Figure 5) is not the result of singular efforts and achievements. It is the result of one’s upbringing, the relationships that developed through the good fortune with one’s friends, teachers, and, most uniquely, with those very special role models, mentors, students, and colleagues. And, certainly, not to be forgotten, they reflect the prior contributions built on the shoulders of earlier scientific investigators that have amassed over a much longer history — at the least over the 391 years since William Harvey’s revelation.

View Large Image Download to PowerPoint

Figure 5. Mosaic of multifactorial factors involved in the relationships on the impact of an individual clinical investigator on his/her contributions to medicine and science.