Edward D. Freis, MD (1912–2005)
With feelings of sadness and thoughts of pride, this communication is written to the hypertension community worldwide to express our honor and to celebrate the life and contributions of Edward D. Freis, MD, who died after a brief illness on February 1, 2005, at the age of 92 years. Ed Freis is widely known as the father of the first multicenter, double-blinded, random trial of cardiovascular drugs, the Veterans Administration Cooperative Study on Antihypertensive Agents. It was his series of studies that demonstrated the efficacy of antihypertensive drug therapy and dramatic reduction of cardiovascular morbidity and mortality for the treatment of hypertensive diseases. This work stands out as a landmark achievement in medicine. Moreover, his efforts to promote national and worldwide attention to the mass treatment of hypertensive patients initiated a new era of public health medicine, preventive cardiology. For the concept and design of the Veterans Administration trials, Edward D. Freis was honored by the Albert Lasker Foundation Clinical Research Award in 1971, the Minot Lecture of the American Medical Association in 1973, the James D. Bruce Award in Preventive Medicine by the American College of Physicians in 1977, the Middleton Award of the Veterans Administration for Medical Research in 1980, the Howard W. Blakeslee Award by the American Heart Association in 1980, and the CIBA Award for Hypertension Research by the Council for High Blood Pressure Research (American Heart Association) in 1981, among many others. It was Freis’ contributions that provided the impetus for the establishment of the National High Blood Pressure Education Program by the National Heart Lung and Blood Institute in 1972, the forerunner of other similar national and international programs. He was an outstanding clinical and basic sciences investigator, a remarkable mentor of numerous leaders of cardiovascular investigators, and a proud and loving father, grandfather, and great-grandfather. ⇓
It was just before his graduation from the University of Arizona in 1936 that Ed Freis made the first major decision of his life when he faced the need to decide on a career in medicine or to continue on with a life of professional golfing. Fortunately for all of us, he decided on medicine and entered Columbia University College of Physicians and Surgeons later that year. After graduating in 1940, he went on to the Boston University’s internal medicine training program at Massachusetts Memorial, Boston City, and Evans Memorial Hospitals, and then a research fellowship with Dr Robert Wilkins. There was a hiatus in his postgraduate training when he served in the United States Air Force, first as the Chief of Laboratory Service at Lincoln (Nebraska) Air Force Base and then as the Chief of the Laboratory Service Rheumatic Fever Research Program; but after his research fellowship with Dr Wilkins, he came to the Washington DC, Mt Alto Veterans Administration Hospital in 1949. Initially as Assistant Chief of the Medical Service, he soon became its Chief; and he also served as the Director of the Cardiovascular Research Laboratory and Professor of Medicine at Georgetown University School of Medicine.
Freis remained at that VA hospital for the remainder of his professional career but, in 1959, Dr William Middleton, Head of the Veterans Administration, named Edward Fries as one of the first Senior Medical Investigators of the entire VA. Soon after assuming this full-time prestigious research position, Ed established the Cooperative Study and the rest of his career is history to all students of hypertension and cardiovascular medical history. It was at this time that I enjoyed my research fellowship with Ed and began a lifetime of close relationship, personally and professionally. It was his mentorship, stimulation, and very special way of relating with his fellows that set a pattern and style for all of us who chose a career to emulate this great physician, teacher, and scientist. His door was always open to discuss any issue with him, providing one initiated the interest and sought out his counsel. Once, when I was invited to participate on an international program on antihypertensive drug trials a number of years ago, the speaker preceding me recounted several flaws in the original VA trial studies. In my rejoinder, I briefly responded that those remarks were like faulting Henry Ford for the design of the Model-T for lacking the improvements of the most recent models.
But Freis’ contributions did not exclusively reside with his designs for the many Cooperative Studies for which his was a “household” clinical name. Several years ago, while I was Editor-in-Chief of Hypertension, I invited Ed to summarize for the journal some of his more well-known studies emanating from his cardiovascular research laboratory. He reviewed his other work on the hemodynamics of congestive heart failure and myocardial infarction, advancing a new concept of “unloading the heart.” How taken back most investigators were at the thought of administering a ganglion blocking agent in these circumstances to reduce left ventricular preload! He first tried out this concept using a mechanical model of the heart that demonstrated improved cardiac performance when venous return was reduced, using his specially constructed venous reservoir. To my more recent (and personal) thinking and amazement were his studies on blood flow velocity that provided more fundamental support to the earlier clinical reports of Alton Ochsner, who used leg compression by an elastic stocking as a prophylaxis against phlebothrombosis in surgical patients by diverting flow from the more superficial veins to deep veins, thus accelerating deep venous flow. His studies on blood pressure in small arteries, on the velocity of red blood cells and other elements in circulating blood compared with plasma, as well as his work on transcapillary migration of other constituents in the circulation were truly innovative. Their design and conduct were not limited to time and could very well be pursued today. These and other ideas were prematurely discontinued when responsibilities for the Cooperative Studies became more onerous. Without his early hemodynamic studies on each of the new classes of agents (ie, ganglion blockers, veratrum alkaloids, diuretics, etc), he would not have had the broader perspective of antihypertensive drug therapy in hypertension. No doubt these experiences allowed him to conceive the concept of combination therapy. Each of these various areas of investigation gave great impetus to those of us who trained with him as well as those who were his research fellows or on our own who later follow through on the foregoing areas as well as with “cardiogenic hypertension,” vascular compliance, plasma volume expansion, and aging. It is remarkable, indeed, to see the beginnings of their studies forecasted in Freis’ classic review of the hemodynamics of hypertension in Physiological Reviews in 1960. I still suggest this review as the first reference to be read by fellows in training.
Clearly, my own interests in the hemodynamics of hypertension must be credited to Ed Freis for its impetus; and Jay Cohn’s and Ed Lakatta’s interests in cardiac unloading and aging, respectively, received their beginnings in their areas of excellence. I invited both for their comments in this article celebrating Ed Freis.
Jay Cohn offered that what I learned from Ed Freis’ mentorship >40 years ago was the virtue of critical, incisive thinking and care in research design. Ed was incredibly disciplined in his life and in his work. His daily routine left little room for spontaneity, from daily naps on his office couch to afternoon golf practice on the field adjacent to the VA Hospital. He tried to teach me a better golf swing, which was his passion. We played rain or shine. One hot day, when I almost collapsed on the thirteenth tee, he left me lying on the grass with a comment that he would come back for me after he finished the back nine. In scientific discussions he cut to the chase. His desktop was always clear because he dealt immediately and efficiently with all mail and messages. I never learned to discipline my life, which is cluttered with books and papers that I never find time to deal with. But the research integrity and intellectual discipline that Ed demonstrated in our daily encounters have had a profound effect on my career.
Edward G. Lakatta wrote, “Ed Freis was my first research mentor. While a medical student at Georgetown University, I had not previously been exposed to research and wished to find out what it was like. Ed’s genuine zeal for research rubbed off on me! We spent substantial periods of time planning experiments, interpreting results, and, subsequently, writing up the findings. He instilled in me the confidence needed to deliver my first paper describing our results at an American Heart Association Meeting, a rare experience for a medical student. Because of my interaction, I developed a passion for research that has never dwindled. Following my training in internal medicine, I spent 2 years at NIH studying cardiac muscle changes with aging. Later, when I was a fellow in cardiology, Ed made another substantial impact on my career. He and others at the Washington VA Hospital had made remarkable contributions to hemodynamics research, and I was poised to commit to this area of research as well. Ed advised me, however, that the door toward understanding the mysteries of the cardiovascular system was not via hemodynamics but in heart cell research, (ie, the type of stuff I had explored at NIH). I heeded this advice and have enjoyed a challenging 30-year career doing so, and following in his footsteps. I am hoping to continue for at least another 20 years!”
Were Robert Tarazi, my first research fellow at the Cleveland Clinic, still alive, I am certain that he would credit Ed’s concept of cardiogenic hypertension for his personal interests in that area.
One of Ed’s first research fellows was John Rose, who became the Chairman of Physiology at Georgetown and later Dean of the Medical School. In reflecting about Ed Freis, John Rose said that he became a research fellow after his internship in 1951 and “I was a close personal friend ever since. He was a remarkable guy, a great teacher: gentle, kind, and prodding. But, in the experimental laboratory of the early 1950s, he was also compulsive, having all of the qualities of a true scientist, intensity and stress when things were not going well!” As a former Dean of the School of Medicine, Rose was justly proud to tell me that Ed donated his Lasker Awards to the University for display. Dr Larry Lillienfield, another research fellow of Freis, succeeded John Rose as Chairman of Physiology and commented, “Ed was a wonderful guy who made a tremendous impact on the fundamentals of cardiovascular physiology as well as the more widely known contributions in the area of clinical hypertension.”
When time came for Ed Freis to step down from his leadership role of the Cooperative Study, he encouraged Barry Materson to succeed him. Materson wrote the following: “I owe him big and I remember telling him that every time that whenever I spoke with him. He was a great mentor even though I never worked directly for him. I enjoyed playing golf with him, and he not only tolerated playing with me but also gave me some lessons in the process. Ed Freis was never swayed by the dogma of the moment unless it was thoroughly back by valid data. He demanded databased opinions long before evidence-based medicine was popularized.”
Another successor to Freis’ hypertension responsibilities was Vasilios Papademetriou at the VA Hospital in Washington. At Ed’s funeral, Vasilios commented in his warm and thoughtful eulogy that “Ed Freis was a good man, someone who served science religiously but also someone who enjoyed life tremendously. He prided himself on knowing every good restaurant in town and particularly every good deal. Confidentially, he told me the best deal was a Greek restaurant called Ambrosia; but, on numerous occasions he commented how much he enjoyed Greek food and in particular my wife’s offerings. Long after he retired from the clinic we shared office space for another decade. He continued his contributions to the literature. He was a great man, and had a good life, a brilliant career, and passed away quietly. Ed, we will miss you. God may rest your soul in peace and God bless you and thanks for coming.”
All of us are the product of the teaching and thinking of our mentors. Therefore, I must add the following comment. When Ed responded to Irvine Page and Arthur Corcoran’s invitation to write a review on the Hemodynamics of Hypertension for Physiological Reviews, I was then Ed’s research fellow. I personally read and re-read 3 entirely different versions from that which was finally published. Each paper was a beautiful lesson to me, but not the one that was finally published. My lesson was clear at the time, not only report your best and most careful work but also take into special consideration the suggestions of your colleagues and reviewers. In that line of thinking, Ed Freis published his last paper in 2004 at the age of 92. I am certain that long after his passing we shall look back on Ed Freis and his remarkable contributions for us all with tremendous respect and admiration for this leader in the history of hypertension.
At this late date, Jay Cohn and I just learned that each of us is to receive the American College of Cardiology’s Distinguished Scientist Award in 2 weeks at its annual convocation, Jay’s in the Clinical Domain, and mine in the Basic Domain. How proud Ed would be of us and, conversely, how thankful we are to him for putting us on our respective roads to our satisfying and exciting careers.