The Robert F. Grover Prize
The Robert F. Grover Prize is given annually "For outstanding contributions to the study of the effects of hypoxia and high altitude on the pulmonary circulation." Dr. Grover had a career-long interest in this field and made many contributions to that area. The endowed prize is maintained by the American Thoracic Society; the winner is chosen by the Awards Committee of the Pulmonary Circulation Assembly and is honored at the annual meeting of that Assembly. In 1994, Dr. Grover received the Edward Livingston Trudeau Medal from the American Thoracic Society. The letter of nomination is included here for it summarized Bob Grover's distinguished career.
Grover Prize Winners
2016 - Marlene Rabinovitch, MD
2015 - Kurt Stenmark, MD
2014 - Peter H. Hackett, MD
2013 - Lorna G. Moore, PhD
2012 - John H. Newman , MD
2011 - Jan Herget, MD
2010 - Johannes Piiper, MD
2009 - Robert L. Johnson, MD
2008 - Javier Arias-Stella, MD, FRCP
2008 - Dante Penaloza, MD
2007 - Jimmie T Sylvester, MD
2006 - Norbert F. Voelkel, M.D
2005 - Ivan F McMurtry, PhD
2004 - Wiltz W Wagner, Jr., PhD
2003 - E Kenneth Weir, MD
2002 - Charles A Hales, MD
2001 - Jack T Reeves, MD
2000 - Peter D Wagner, MD
NOMINATION FOR THE EDWARD LIVINGSTON TRUDEAU MEDAL - 1994
Robert F. Grover
1. Major scientific contributions.
Robert F. Grover, M.D., Ph.D. has made major scientific contributions in the area of hypoxia and its effect on the oxygen transport system. He has extensively investigated the hypoxia resulting from hypoventilation and high altitude and the sequelae of long-term hypoxemia such as polycythemia. Specific areas of investigation have included control of the pulmonary circulation, control of breathing, and regulation of cardiac output.
Control of the pulmonary circulation. Throughout his career, Dr. Grover has been at the forefront in the work on understanding the physiologic mechanisms underlying hypoxic pulmonary vasoconstriction, the regulation of pulmonary gas exchange (ventilation-perfusion matching), and hypoxic pulmonary hypertension. On the latter topic, much of his early work demonstrated the variability both between species and among individuals of the same species. He was the first to document significant pulmonary hypertension in the high altitude residents of North America in Leadville, Colorado (10,200 ft). Over 30 years ago he achieved international recognition by organizing the 1962 Aspen Lung Conference on the pulmonary circulation. At that meeting his findings in Leadville were compared with those from the Andes presented for the first time in North America by the Peruvian investigators. Also presented were his pioneering studies in comparative physiology which demonstrated that cor pulmonale developed in otherwise normal cattle when they were transported to high altitude. Those early animal studies established the bovine calf as an excellent animal model for the study of hypoxic pulmonary hypertension. Later, he demonstrated that among cattle exposed to chronic hypoxia, pulmonary vascular hyper-reactors and hypo-reactors were inherited traits. This concept has proven valid for other species including humans.
Dr. Grover instigated or performed studies on a variety of factors that could influence acute or chronic hypoxic pulmonary hypertension: sympathetic nervous activity, exposure to cold temperatures, prostaglandins, endotoxin, acetylcholine, ethyl alcohol, increased blood flow, histamine, and activation of platelets and mast cells. In collaboration with Dr. Ivan McMurtry he was among the first to obtain evidence that hypoxia did not act through a chemical or nervous mediator but rather acted directly on the pulmonary vascular smooth muscle cell. Others have since extended those observations leading to the development of the entire field of investigation of the influence of hypoxia on ionic channels.
Control of breathing. It was Dr. Bruce Dill who stimulated Drs. Grover and Reeves 30 years ago to initiate studies of the control of breathing in athletes during exercise. This work compared sea level residents with Leadville natives at both high and low altitude. Because this landmark study immediately preceded the 1968 Olympic Games in Mexico City, that work established Dr. Grover in the realm of Sports Medicine. Subsequently he became a Fellow in the American College of Sports Medicine. Dr. Grover and his wife collaborated not only on the studies of athletes in Leadville, but also on studies of exercise and ventilatory control in Quechua Indians of the Peruvian Andes, Aymara Indians of the Bolivian Andes, and later Sherpas of the Himalayas. In Colorado, Dr. Grover, Dr. John Weil, and others documented variability among individuals in the ventilatory response to acute hypoxia. This led to the important concept that a low hypoxic ventilatory response does not cause hypoventilation; rather, it is permissive, allowing hypoxemia to persist when some other extrinsic factor such as obesity or chronic obstructive pulmonary disease leads to hypoventilation. Dr. Grover demonstrated that the low hypoxic ventilatory response characteristic of adult residents of high altitude is acquired during years of exposure to chronic hypoxia, because it is not present in children born in Leadville.
Regulation of cardiac output. Many investigators have observed that human physical working capacity, as measured by maximal oxygen uptake, is decreased at high altitude. Dr. Grover, working with Dr. J. K. Alexander, demonstrated for the first time that following ascent to high altitude, cardiac stroke volume decreases in association with the shrinkage of plasma volume and consequent reduction in blood volume. Subsequently, Dr. Grover established that the normal hemoconcentration and decrease in stroke volume on exposure to high altitude were dependent on the associated hypocapnia that results from hyperventilation. With continued residence at high altitude, hypoxia via erythropoietin stimulates the production of additional red blood cells (secondary polycythemia). In Dr. Grover's most recent investigation, he and his colleagues demonstrated that the net increase in red cell volume at high altitude is variable among individuals. When it does occur, it offsets the decease in plasma volume and preserves blood volume; when it does not occur, blood volume decreases. This has important implications for cardiovascular function and the decrease in exercise capacity.
Drs. Grover and Alexander showed through direct measurements of the coronary circulation that the fall in stroke volume was not a consequence of myocardial hypoxia. Further, they found that in the normal heart, coronary flow actually decreases (along with cardiac output) at high altitude. Physiologically, this decrease in coronary flow is required to preserve the constancy of coronary venous (myocardial tissue) oxygen tension in the face of a decrease in the affinity of hemoglobin for oxygen (right shift) caused by an increase in red cell 2,3-DPG. This may be beneficial to patients with coronary artery disease and limited capacity to increase coronary blood flow.
2. Accomplishments as a teacher and significant accomplishments of his/her trainees.
Dr. Grover's early career interest in the adaptations to hypoxia has been the overriding theme for the Cardiovascular Pulmonary Research Laboratory and indeed for many investigators at the University of Colorado. Under the umbrella of hypoxia, several issues have naturally come together, including the pulmonary circulation, control of breathing, oxygen transport (at altitude, in exercise, with pregnancy, and in the fetus), lung injury, and more recently, tissue, chemical, cellular, and molecular mechanisms of hypoxia. These themes, developed under his direction, have persisted since his retirement, and have led to remarkable findings and outstanding careers. While he was a research fellow, Ivan McMurtry reported the calcium dependence of the hypoxic pulmonary vasoconstriction mechanism. His later work has included the histology and pathophysiology of endothelial control of smooth muscle tone. The recent successful application of nitric oxide to neonatal pulmonary hypertension in Colorado can be traced back to McMurtry's intellectual stimulation and encouragement of Dr. Steve Abman, who in a very real sense is Dr. Grover's academic grandson. Dr. Kenneth Weir developed an interest in hypoxic vasoconstriction while in the Cardiovascular Pulmonary Research Laboratory under Dr. Grover's encouraging tutelage. Recently, Dr. Weir found that hypoxia-induced closure of voltage-gated potassium channels depolarizes pulmonary vascular smooth muscle cells thereby setting the stage for calcium entry and vasoconstriction. Dr. John Weil, currently the director of the Cardiovascular Pulmonary Research Laboratory developed his interest in hypoxic control of ventilation as a result of Dr. Grover's altitude experience and the presence of skilled bioengineers in the laboratory. Dr. Lorna Moore's research expertise in high altitude pregnancy developed, in large part, because she came to Colorado to work in Dr. Grover's laboratory and became fascinated by the problems under study and the academic environment available to study them. Dr. Norbert Voelkel came for research training from Germany, but found the intellectual environment so exciting in Denver that he remained to become a world leader in lipid mediators and pulmonary disease. Dr. John Reeves came to the laboratory intending to learn in one year cardiac hemodynamics and cardiac catheterization, but because of Dr. Grover, he remained in academia and has had a remarkably productive career studying many aspects of the pulmonary circulation and the effects of high altitude. Dr. Wiltz Wagner came to the laboratory with only a high school diploma, but was so encouraged that he went on for his Ph.D. in physiology, and has subsequently gained an international reputation for his studies of blood flow in the pulmonary microcirculation. The list of prominent academicians is extensive and includes: Gerald Bisgard, Ronald Capen, Mark Gillespie, Peter Hackett, Jan Herget, Carol Hirshman, Thomas Hyers, Michael Kay, Meir Kryger, Johannes Mlczoch, John Newman, Sharon Rounds, Kurt Stenmark, Alan Tucker, David White, and Clifford Zwillich.
The key for such an outstanding training record lies primarily in Dr. Grover's belief that the enthusiasm and brilliance which young people bring to research must find the thoughtful encouragement that develops the best in each person. There is no doubt that Dr. Grover has been an innovative, careful, and productive investigator. His curriculum vitae attests to that. But his primary talents and those which caused the Cardiovascular Pulmonary Research Laboratory to be built into a laboratory of national and international prominence were his abilities to develop an extensive network of collaboration inside and outside the laboratory while quietly challenging each person to their maximal ability. It is not an overstatement to say that he was not only respected for his judgement, but that he was loved for the interest he showed in everyone: the faculty, fellows, technicians, secretaries, and the maintenance staff. Indeed the daily morning conferences by the research fellows and faculty were required to be clear enough that the entire laboratory could understand even the most complicated finding. Clarity of presentation was deemed a manifestation of clarity of thought. The combination of these qualities built a laboratory where people worked together to make a team much greater than the sum of its individuals. The gratitude which the laboratory faculty felt toward him led to the establishment of the Grover Conference on the Pulmonary Circulation which meets every second year in Colorado and is dedicated to bring to investigation of the pulmonary circulation the best of international science. One mark of true success in science is to instill the excitement of inquiry and motivation to persevere into the next generation. Dr. Grover has done that.
PULMONARY RESEARCH FELLOWS TRAINED BY ROBERT F. GROVER FROM 1965 - 1982
- John T. Reeves Professor of Medicine and Pediatrics, University of Colorado Health Sciences Center, Denver
- John H.K. Vogel Professor of Medicine, University of Southern California Medical School, Santa Barbara
- Wiltz W. Wagner, Jr. V.K. Stoelting Professor of Anesthesiology, Indiana University School of Medicine, Indianapolis
- Eric D. Silove Consultant Paediatric Cardiologist, Children's Hospital, Birmingham, England.
- L. Howard Hartley Professor of Medicine, Harvard Medical School, Boston
- John V. Weil Professor of Medicine, University of Colorado Health Sciences Center, Denver
- Hector Alverez Cardiologist, Los Angeles
- Gerald E. Bisgard Professor and Chairman of Comparative Bioscience, Veterinary Medical School, Madison
- Edward Byrne-Quinn Associate Professor of Medicine, University of Arizona College of Medicine, Tucson
- Toshio Sekimoto Professor and Chief, Cardiovascular Division, Shizouka Red Cross Hospital, Japan
- John R. Meyer Professor of Biology, Los Angeles Baptist College, Los Angeles
- Richard Carson Cardiologist, Denver
- Gunnar Sodol Cardiologist, Oslo
- Callis G. Morrill Research Associate, University of Missouri Medical College, Kansas City
- John Michael Kay Professor of Pathology, McMaster University, Hamilton, Ontario
- Carol Hirshman Professor of Anesthesiology, Anesthesia and Environmental Sciences, Johns Hopkins Med Institute, Baltimore
- Gunnar Strom Cardiologist, Oslo
- Wesley W. Hiser Cardiologist, Wyoming
- E. Kenneth Weir Professor of Medicine, University of Minnesota Medical School, Minneapolis
- Philip C. Weiser Director, Pulmonary Diagnostic and Rehabilitation Department, Medical College of Pennsylvania, Philadelphia
- Ivan McMurtry Professor of Medicine, University of Colorado Health Sciences Center, Denver
- Alan Tucker Professor of Physiology and Assistant Dean, Colorado State University, Ft. Collins
- Clifford Zwillich Professor of Medicine, Chief of Pulmonary Division, Pennsylvania State University Medical School, Hershey
- Meir Kryger Professor of Medicine, University of Manitoba, Winnipeg
- Johannes Mlczoch Chairman, Pulmonary Circulation Group, European Society of Cardiology, Vienna
- Robert C. Doekel Cardiologist, Nashville
- Charles Scroggin CEO, Somatogen Corporation, Boulder
- Eric Hoffman Associate Professor of Radiology and Physiology, University of Iowa College of Medicine, Iowa City
- Robert Looga Professor, Tartu, Estonia
- Bruce J. Martin Associate Professor of Physiology, Indiana University, Bloomington
- Sharon S. Rounds Associate Professor of Medicine, Chief Pulmonary Section, Brown University Medical School, Providence
- Jan Herget Professor and Chairman of Physiology, Charles University Medical School, Prague
- Thomas Hyers Professor of Medicine, Director of Pulmonary Medicine, Saint Louis University Medical School, St. Louis
- David Collins Clinical practice, North Carolina
- Stephen Hammill Associate Professor of Medicine, Mayo Medical School, Rochester
- T. Scott Johnson Assistant Professor of Medicine, Harvard Medical School, Boston
- Ronald L. Capen Professor and Chairman, Biology Department, The Colorado College, Colorado Springs
- C. Edward Rose Associate Professor of Medicine, University of Virginia School of Medicine, Charlottesville
- Norbert Voelkel Professor of Medicine, University of Colorado Health Sciences Center, Denver
- Lorna G. Moore Professor of Anthropology, University of Colorado, Denver
- John H. Newman Elsa S. Hanigan Professor of Pulmonary Medicine, Vanderbilt Medical School, Nashville
- Julio C. Cruz Associate Professor of Anesthesiology and Physiology, Medical College of Ohio, Toledo
- Takayuki Kuriyama Professor of Medicine, Chiba University Medical School, Japan
- Edward J. Morgan Associate Professor of Medicine, University of Hawaii, Honolulu
- Peter H. Hackett Director, Denali Medical Research Project, Anchorage
- Mark N. Gillespie Professor of Pharmacology, University of Kentucky Medical School, Lexington
- Kenneth H. Weisiger Pulmonologist, Denver
- Gregory J. Redding Associate Professor of Pediatrics, University of Washington, Seattle
- Frederick N. Hanson Cardiologist, Minnesota
- Ira M. Dauber Cardiologist, Denver
- Neil J. Douglas Cardiologist, Edinburgh
- David P. White Associate Professor of Medicine, University of Colorado Health Sciences Center, Denver
- Mark D. Petrun Pulmonologist, Ft. Collins
- Takashi Sugita Vice President, Chiba Hospital, Chiba, Japan
- Irwin Shelub Cardiologist, San Francisco
- William T. Pluss Assistant Professor of Medicine, University of Colorado Health Sciences Center, Denver
- James K. Alexander Professor of Medicine, Baylor College of Medicine, Houston
- Shao Yung Huang Research Associate in Anesthesiology, University of Colorado Health Sciences Center, Denver
- Edward M. Canham Cardiologist, Denver
- Kurt Stenmark Associate Professor of Pediatrics, University of Colorado Health Sciences Center, Denver
3. Recognition received nationally and internationally.
Because of Dr. Grover's extensive research into the cardiovascular and pulmonary aspects of human and animal adaptation to high altitude, he is known internationally as an expert in these fields. In recognition of this, in 1992 he received the annual Honor Award from the Environmental and Exercise Physiology Section of the American Physiological Society for his outstanding contributions in these areas. Further, the editors of the standard text in cardiology, The Heart, J. Willis Hurst editor-in-chief, invited Dr. Grover and his associates to write the chapter on "The influence of environmental factors on the cardiovascular system."
For his contributions to our understanding of the pulmonary circulation and the interactions between the lung and the heart, the Cardiopulmonary Council of the American Heart Association selected Dr. Grover for the annual Dickinson W. Richards Award in 1984. Further, he and his associates were invited to write the chapter on the Pulmonary Circulation for the Cardiovascular Section of the Handbook of Physiology. Two of Dr. Grover's friends and longtime associates, Dr. E. Kenneth Weir and Dr. John T. Reeves, established the biennial Grover Conference on the Pulmonary Circulation in 1984. These have proven to be of the highest scientific quality. Six have been held to date; the 7th will take place in 1994.
Repeatedly over the past 39 years, Dr. Grover has been invited to speak at many scientific conferences both in the United States and abroad. He has been a visiting professor at numerous medical schools. He is listed in Who's Who in America, American Men and Women of Science, and has been elected as a Fellow in the American College of Physicians, American College of Cardiology, American College of Chest Physicians, and American College of Sports Medicine.
4. Impact on Clinical Medicine
One of Dr. Grover's major contributions to clinical medicine has been to increase our understanding of adaptation to moderate altitude. Because millions of people ranging from infants to the elderly, some of whom have cardiovascular disease, vacation at moderate altitudes each year, this area of research is important. Dr. Grover established the only laboratory in the world with a major emphasis on moderate altitude (8,000-12,000 ft), unlike others who have focused on the limits of human tolerance to extreme altitude (>20,000 ft).
Pulmonary hypertension. Dr. Grover made the first measurements of pulmonary arterial pressure in normal residents of Leadville, demonstrating that elevated pressures in this setting were a normal physiological response to the chronic atmospheric hypoxia, that the pulmonary hypertension was benign, well tolerated, and not progressive, and that it was reversible upon descent to low altitude. Hence it should not be considered a pathological condition and mistakenly diagnosed as either primary pulmonary hypertension or cor pulmonale.
Dr. Grover, together with Dr. Hultgren, made the first measurements of pulmonary vascular reactivity in persons susceptible to high altitude pulmonary edema; they are not hyper-reactors at sea level, but they do have an inordinate rise in pulmonary arterial pressure upon exposure to high altitude. Dr. Grover was involved in demonstrating that sustained elevation of pulmonary blood flow, as in congenital unilateral absence of one pulmonary artery, when combined with mild airway hypoxia, leads to marked pulmonary hypertension. He also reported that persons with this congenital abnormality are unusually susceptible to high altitude pulmonary edema.
Pulmonary vascular reactivity during pregnancy was another area of interest for Dr. Grover. He made the first measurements of the pulmonary vascular response to prostaglandin F2 in pregnant women undergoing abortion with this agent. His studies also showed that pregnancy induces pulmonary hypertension in cattle.
In sum, the articles that he has written or co-authored provide a considerable part of our current understanding of the pulmonary circulation.
Hypoventilation. Dr. Grover emphasized the importance of variability in various responses to hypoxia. This included the normal spectrum of ventilatory responsiveness to acute hypoxia. He found that just as for pulmonary vascular responsiveness, there are ventilatory hypo-responders and hyper-responders, traits that are inherited. These insights led to the understanding that in patients with obstructive airway disease, those with inherited ventilatory hypo-responsiveness will develop airway hypoxia, and if they also inherited pulmonary vascular hyper-responsiveness they will then develop hypoxic pulmonary hypertension which may ultimately lead to cor pulmonale. Further, these are the patients who will develop polycythemia and become "blue bloaters." Conversely, those patients with chronic obstructive pulmonary disease who inherit ventilatory hyper-responsiveness to hypoxia combined with pulmonary vascular hypo-responsiveness will present as "pink puffers."
Excessive polycythemia is a common problem among men living at moderate altitude in Leadville. Hypoventilation during sleep causing marked hypoxemia appeared to be the etiology. Together with Dr. M.H. Kryger, Dr. Grover established that chronic ventilatory stimulation with medroxyprogesterone acetate would correct the hypoventilation leading to resolution of the polycythemia. Treatment over several years proved the sustained effectiveness of this therapy.
Acute mountain sickness is common among visitors to high altitude. Symptoms include headache, insomnia, anorexia, nausea, and vomiting. More serious is high altitude pulmonary edema, which we now realize is not as uncommon as believed formerly. Dr. Grover and his associates demonstrated that many who suffer from both of these disorders have a poor ventilatory adaptation to altitude, with associated fluid retention, and that acetazolamide as a ventilatory stimulant (and mild diuretic) is effective prophylaxis.
Coronary artery disease. Many older individuals visiting moderate altitudes have some degree of coronary arterial disease. This raises the question of whether moderate altitude is an added risk factor. Based on Dr. Grover's studies of the human coronary circulation combined with his clinical field studies, the evidence indicates that there is no special risk for the patient with a reasonably good exercise tolerance at sea level.
To summarize, for the last four decades, Bob Grover has been an outstanding scientist, for which he has a well-deserved international reputation. His investigations have impacted not only on basic pulmonary physiology and pathophysiology, but have also had important clinical relevance. Of perhaps the greatest significance to Dr. Grover himself is that of 60 young scientists he trained, 43 have remained in academia. Among the academics, 25 have thus far achieved the rank of full professor and 20 are deans, chairmen, division chiefs, or program directors.
Wiltz W. Wagner, Jr., Ph.D., Indianapolis
John T. Reeves, M.D., Denver