Just as a great symphony is only an elegant idea until it is actually performed, groundbreaking biomedical research is only of potential value until it is actually applied.
Perhaps more than any other academic physician, Eugene Braunwald, M.D., has guided the movement of cardiovascular research—recognizing the significance of disparate results and pushing the field forward from bench to bedside. Like a conductor who understands the importance of each note in a symphony, Braunwald is viewed by many as the “grand maestro” of American cardiology.
“He led a series of studies that transformed the face of cardiovascular medicine,” says Douglas Vaughan, M.D., former chief of Cardiovascular Medicine at Vanderbilt University Medical Center. During the past 25 years, in part because of research led by Braunwald, the percentage of people who die within a month of being hospitalized for a heart attack has plunged five-fold, from 20 percent to about 4 percent.
“That is an enormous difference,” says Vaughan, who was part of Braunwald’s research team in the late 1980s. “Every practicing cardiologist has to appreciate the impact of Dr. Braunwald’s insights and research in the mechanisms and treatment of acute myocardial infarction (AMI).”
Braunwald struck his first international chord as the lead author of a 1971 landmark study showing, in an experimental model, that the damage caused by AMI, a heart attack, could be limited by favorably altering the balance between the supply of and demand for oxygen in the heart.
Until that discovery, physicians had believed that once a patient exhibited symptoms of crushing chest pain, little could be done to affect the outcome. When patients with AMIs were rushed to the hospital, they were sedated, put on strict bed-rest and, if necessary, defibrillated. If they survived, they were sent home on various medications. During the next year, a quarter of the survivors died, usually of heart failure.
Braunwald was the first to challenge this laissez-faire approach to AMI. In 1967, while visiting the laboratory of Seymour Schwartz, M.D., a surgeon at the University of Rochester, he was shown dogs with experimentally-induced hypertension. Implanted stimulators of the animals’ carotid sinus nerves restored their blood pressures to normal.
At the time, Braunwald, at the ripe old age of 38, had already been chief of cardiology at the National Heart, Lung and Blood Institute, part of the National Institutes of Health (NIH), for eight years. Immediately, he and his colleagues began implanting stimulators of the carotid sinus nerves in patients, but for a totally different reason—to relieve angina pectoris (chest pain). Although this treatment worked, it was short-lived because of the near simultaneous introduction of coronary bypass surgery, which was a preferable way to correct the imbalance between the heart’s supply and consumption of oxygen.
However, a year later, serendipity came into play. One of Braunwald’s patients with an implanted carotid nerve stimulator was admitted to the hospital with an AMI. Fearing that stimulating the carotid sinus nerves would exacerbate the evolving MI, Braunwald asked the patient to turn off the device. The patient ignored him and continued to press the stimulator to relieve his pain. Eventually, after several “on-off” episodes, Braunwald, in exasperation, removed the stimulator’s battery pack.
Later, when he was reviewing the patient’s electrocardiogram, which had been recorded throughout this period, Braunwald realized that the “patient was a lot smarter than I.” The oxygen deficiency of his patient’s heart actually improved whenever he stimulated his carotid sinus nerves, and worsened when Braunwald turned off the stimulator—the exact opposite of what he had expected. He was thunderstruck.
“That gave me the idea that you might actually be able to modify an MI while it is progressing,” says Braunwald.
Sound of music
Eugene Braunwald was born in Vienna, Austria, on August 15, 1929. He had what he terms an “idyllic childhood” as the firstborn son of a well-to-do Jewish wholesale clothing merchant, William Braunwald, and a homemaker mother, Clara, living in a fine neighborhood, attending an excellent private school, tutored in English and piano, and beginning to partake of the famed cultural offerings of Vienna.
Braunwald’s life took a chilling turn on March 12, 1938, however, when the Nazis occupied Austria. He was immediately expelled from school.
Only a few days later, an SS officer arrived at the Braunwald home (which was attached to the business) and methodically set about liquidating the business holdings, keeping the profits for himself. Two months later, a group of Nazis barged into the home at around 3:00 a.m. and arrested William Braunwald, throwing him into a truck and carting him and other detainees to the train station to be shipped off to a “work” camp.
Clara Braunwald was frantic, but she kept her wits about her. The next morning when the SS officer arrived, she told him that her husband had been arrested, which was unfortunate because the officer had liquidated only half of the business. She pointed out that he could become much wealthier if her husband’s deportation could be delayed until the entire stock was sold.
“You might be right,” the officer mused. He then made a phone call or two, ordering William Braunwald to be returned home.
On July 31, 1938, William and Clara Braunwald packed some lunches and told Eugene and his younger brother Jack that they were going on a picnic. They boarded a trolley, then a taxi, then a train, and eventually crossed into Switzerland. From there they traveled to Paris, and finally wound up in London as wards of a relief agency, in possession of nothing more than the proverbial clothes on their backs.
“It was like the Sound of Music, except there was no music,” Braunwald says, admitting that they barely made it out in time. “Kristallnacht (the wave of pogroms against German and Austrian Jews) came three months later.
“This was a point of no return; Jews were slaughtered on the streets, others were arrested and carted off wholesale to concentration camps. It was the start of the Holocaust. But I was very lucky. I never went hungry and I had no physical injury. So, given the whole scale of things, I feel extremely fortunate.”
Their fortunes detoured again during the London blitz. Because Austrian refugees were deemed “enemy aliens” in Britain, the Braunwalds had to leave the country or be interned in work camps. They managed to get to New York City, where they had a relative. They arrived the day after Thanksgiving 1939.
Two years later, the United States entered World War II. For young men and women on the home front, the catchword of the day was “engineering.” Joining this wave, Braunwald was accepted into the elite Brooklyn Technical High School, in an accelerated program in which both high school and college could be completed in five years.
At New York University, however, Braunwald decided he was more interested in biology than engineering. He wanted to become a physician.
Getting into medical school was much more difficult than it is today. At the time, medical schools had strict quotas limiting the number of Jewish enrollees, and returning war veterans (appropriately) were given first priority. Braunwald was the last student admitted to New York University’s medical school class of 1952. (He was also the first out, graduating as the top student in his class).
“My admission to medical school was the most important day of my professional life,” he says. “All the pressures were behind me. I loved every moment of medical school.”
Like many financially disadvantaged students of that era, Braunwald, on a full tuition scholarship, lived at home and commuted by subway, toting his microscope, slides, Gray’s Anatomy, and box of cadaver bones back and forth with him to class every day.
Also, for the first time since he left Vienna, Braunwald took advantage of the outstanding musical performances the city had to offer. He volunteered to be an “extra” at the Metropolitan Opera, and was paid a dollar a night for his role as a spear-carrier in the Met’s productions of Aida and La Tosca. He gave up his “operatic career” once he began his internship.
Electricians and plumbers
Braunwald’s instructors at NYU included two Nobel laureates: fellow Austrian exile Otto Loewi, M.D., recognized for seminal discoveries relating to the chemical transmission of nerve impulses; and pioneering molecular biologist Severo Ochoa, M.D.
Braunwald also studied under Colin MacCleod, M.D., who co-authored the pivotal 1944 paper that established DNA as the bearer of hereditary information, and Homer Smith, M.D., a founding father of comparative physiology and nephrology. Medical history, says Braunwald, “was unfolding all around me. Luckily, I realized what was going on.”
In the early 50s, NYU had originated the then novel (and now commonplace) practice of offering a three-month elective to medical students. With the engineering mantra playing in his memory, Braunwald chose for his elective a research rotation in cardiology, studying the hemodynamics of heart failure under the guidance of Ludwig Eichna, M.D., who ran one of the nation’s first research cardiac catheterization laboratories.
“Cardiology is in many ways a hybrid between engineering and biology,” Braunwald says. “Cardiologists can be divided into electricians and plumbers. Those who deal with rhythm disturbances are the electricians and those who deal with disturbances of cardiac pumping are the plumbers.” Disturbances in the operation of either the rhythm or the pump can cause the heart to fail.
The weekend after graduating from NYU medical school, Braunwald married his college and medical school classmate, Nina Starr Braunwald (1928-1992), who would later achieve pioneer status as a cardiothoracic surgeon. In 1960, she would lead the first team to successfully replace a human heart valve, which she had designed.
After a residency at Mt. Sinai Hospital in New York, Braunwald spent a research fellowship year at Columbia University and Bellevue Hospital, studying under André Cournand, M.D., soon also to win a Nobel Prize for advances in cardiac catheterization.
He completed his medical residency in internal medicine at Johns Hopkins Hospital, where he attended lectures given by cardiovascular giants including Alfred Blalock, M.D., and Helen Taussig, M.D., who had just developed the “blue baby” operation. Then he went on to the intramural program of the NIH.
In 1967, Braunwald became an editor of Principles of Internal Medicine, now considered to be the defining medical text for physicians and medical students around the world.
Launched in 1950 by former Vanderbilt professor Tinsley Harrison, M.D., Principles offered medical students a new way of approaching patients. Instead of describing various diseases as earlier textbooks had done, Harrison’s book invited students to understand the biologic basis of signs and symptoms which would lead to correct diagnosis and rational treatment. This textbook was the first to break down the wall between basic science and clinical medicine.
The same year, Braunwald got the chance to apply this new approach to medical education when he was asked to become the founding Chairman of Medicine of the new medical school at the University of California at San Diego (UCSD). He seized the opportunity and moved his family, which now included three daughters, to the West Coast.
Braunwald and his colleagues immediately set about bridging the educational divide that existed universally at the time. Surgeons taught anatomy; internal medicine faculty taught physiology and pharmacology. The head of the infectious disease division taught microbiology, as well as clinical infectious diseases. Their approach, which was quite controversial at the time, is now the cornerstone of medical education throughout the country.
Meanwhile, the research in the Braunwald laboratory was going well. His team published key studies on AMI in dogs showing that giving a beta blocker to lower myocardial oxygen demand and reperfusion to increase oxygen supply reduced the size of the MI. This laid the groundwork for a standard of care that was revolutionary at the time, but which still holds today—namely, that aggressive medical intervention before, during and after a heart attack can reduce myocardial damage and therefore be life saving.
Four years later, after overseeing the graduation of UCSD’s charter medical school class, Braunwald was called back to the East Coast, this time to Boston, to chair Harvard University’s Department of Medicine at the Peter Bent Brigham Hospital (now Brigham and Women's Hospital). Over time, he held increasingly complex positions, including eight years as Harvard Medical School’s Faculty Dean for Academic Programs at Brigham and Women’s and Massachusetts General Hospitals.
But his devotion to cardiovascular research never wavered.
The next frontier
By the end of the 1970s, the injection by catheter of a thrombolytic (clot-busting) agent, streptokinase, into blocked coronary arteries was just beginning to take hold. In 1981, Braunwald’s team showed for the first time that when streptokinase was used in this manner to open blocked arteries, myocardial tissue threatened during an AMI could be salvaged by restoring the supply of oxygen-laden blood.
The question then became how to administer these thrombolytic drugs intravenously, so that patients could receive medication as quickly as possible, even away from the hospital—in an ambulance, if possible. Streptokinase worked fine when given through an intracoronary catheter, but it performed poorly as an intravenous therapy.
In the early 1980s, a new class of recombinant-DNA drugs was developed, including the thrombolytic agent, tissue plasminogen activator (tPA), which was effective when delivered intravenously. Braunwald was certain that tPA and the concept of on-site, immediate treatment of evolving AMI was the next frontier, and he prevailed on the NIH to let him set up a clinical trials network to test this theory.
In 1984, he established the first TIMI (Thrombolysis in Myocardial Infarction) study, which found that intravenous tPA was indeed superior to streptokinase in opening occluded arteries. With more than 800 sites in 46 countries participating in subsequent TIMI studies, today Braunwald is viewed as one of the world’s masters of the clinical trial.
“Ask anybody who’s ever worked for Dr. Braunwald. The best work you’ll ever do is when he is standing behind you, looking over your shoulder,” says Marc Pfeffer, M.D., Ph.D., professor of Medicine at Brigham and Women’s Hospital. “He sets high standards, but he lives by those standards, too.”
Pfeffer and his late wife, Janice Pfeffer, Ph.D., came to Boston in the mid-1970s to pursue studies of left ventricular enlargement (also called hypertrophy), associated with systemic hypertension and by AMI with Braunwald.
By the early 1980s, they had established that captopril, an angiotensin converting enzyme (ACE) inhibitor, developed to control hypertension, also reversed hypertrophy and improved cardiac performance and survival in rats with MI. Their findings led to the Survival and Ventricular Enlargement (SAVE) clinical trial, which in 1992 showed that ACE inhibitors improved the left ventricular function and reduced mortality in patients who’d suffered a major heart attack.
Today, ACE inhibition is routinely recommended for patients following an MI, and is given to millions of such patients worldwide each year.
By 1988, doctors knew that patients with elevated low-density lipoprotein (LDL) cholesterol tended to be at risk for recurrent MI. In another study, the Cholesterol and Recurrent Events (CARE) trial, Braunwald and his colleagues studied whether heart attack patients with “average” cholesterol levels (at the time, 210 milligrams per deciliter of blood), also would benefit from taking cholesterol-lowering drugs.
For five “nail-biting” years, Braunwald’s team waited for the results, which ultimately showed that patients who took pravastatin to lower serum cholesterol indeed reduced their risk for having another heart attack, stroke, or dying of cardiovascular causes.
More recent TIMI trials have examined the effect of driving cholesterol levels even lower, and have found not only that “lower is better,” but that “much lower is much better.” TIMI investigators are currently studying the effects of reducing a patient’s LDL to a level in the 50s, levels undreamed of ten years ago.
“We’ve followed all of these patients extremely carefully and we don’t see any serious side effects with even extreme cholesterol lowering,” says Braunwald. “We have not yet reached the (LDL-concentration) floor.”
For more than a half century as an academic physician-scientist, Braunwald has been instrumental in numerous discoveries that have saved millions of lives, and, for the record, he has no plans to stop anytime soon.
Now married to his second wife Elaine, formerly a senior hospital administrator, and a grandfather of seven, he is editing Harrison’s for the eleventh time and is leading methods for moving the textbook into the digital age. He is also piloting new TIMI trials, including several that test the therapeutic potential of novel anti-platelet agents.
He and his team recently began active planning of the fiftieth TIMI trial, even as he ponders how genetics and information technology will rewrite the score of cardiology.
“The principal task of the cardiologist in 2007 is to diagnose, assess, and treat established cardiovascular disease,” he says. “As a consequence of the revolution in human genetics, the principal role of the cardiologist by 2027 will be to interpret the patient’s genetic information and from this develop a plan personalized for each patient for the prevention of cardiovascular disease.”
Braunwald has left a huge imprint on basic science, translational research, clinical trials, and medical education. He has moved easily between the laboratory, the bedside and the classroom. But perhaps his true genius lies in his ability as the “grand maestro” of cardiology to comprehend the big picture, even as he stands in the middle of it—responding to tones, harmonies and nuances in the cavalcade of processes that are unique to the beating heart.