Authors: James Forrester
The Heart Healers (32 page)
Collaborating with Collen they were able to successfully clone the gene responsible for expression of t-PA, using cells originally derived from a Chinese hamster ovary. Again they were able to manufacture industrial quantities, this time it was t-PA. At that time, a young medical resident was finishing his training at nearby University of California in San Francisco Hospital. Collen’s manuscript describing use of t-PA in dogs was the subject of one of the residents’ weekly journal club meetings, where interesting articles were selected for discussion. Dr. Eric Topol, later to become a thought leader in his generation of cardiologists, describes his reaction:
I was struck by the idea that (t-PA) could be used for acute myocardial infarction. I inquired further and was told to contact a lady named Diane Pennica at Genentech. Busy with plans for starting cardiology fellowship at the Johns Hopkins Hospital, I forgot about (t-PA) until I was packing and found her name scribbled on a slip of paper. I called her and was introduced to the members of the Genentech team. Although I moved to Baltimore to start my fellowship, I was soon contacted by Bob Swift at Genentech, and began a collaborative effort to use t-PA for acute MI. In February, 1984, my colleagues and I successfully treated the first patient with recombinant t-PA at the Johns Hopkins Hospital, a 57-year-old woman with an acute occlusion of her left anterior descending artery (in lay language, a clot in the coronary artery we earlier nicknamed “the widow maker”).
Topol subsequently became the principal investigator on a large randomized trial in myocardial infarction. The trial reported that t-PA more rapidly opened coronary arteries than streptokinase, with a modest reduction in mortality.
Now a fierce transatlantic debate erupted, because t-PA was about ten times more expensive than streptokinase. At the 1991 American College of Cardiology scientific sessions, American t-PA advocates presented their data in the convention center’s packed massive main auditorium. When the British, sensitive to the cost of the new drug, wholeheartedly disagreed with the Americans, a scientific shouting match erupted. The debate was heated.
The real nastiness, however, came days later when the ABC-TV public affairs program
20/20
railed against the high cost of t-PA, then revealed a financial relationship between Genentech and Dr. Burton Sobel, the editor of
Circulation,
one of cardiology’s most prestigious journals. I soon learned from personal conversations that a number of American cardiology’s thought leaders had quietly been given shares in Genentech as consultants. Dr. Arnold Relman, editor of
The New England Journal of Medicine,
jumped into the combustible relationship between academic medicine and industry with both feet. Relman was infuriated by the incursion of industry into the formerly pristine practice of medicine: “Editors and their staffs should be totally free of conflicts of economic interest. They should have no economic connection at all with any health related company,” he said. As the debate raged on, Eric Topol, who had led a much-quoted trial of t-PA, added, “Streptokinase is the gold standard drug. t-PA, while a very good thrombolytic agent, is not worth over $2,000 per dose.” The program foreshadowed a new and terribly serious moral conundrum, which we thought leaders were about to confront, the relationship between academe and industry. This issue dominates the ethics of today’s health care. At that time, however, Relman’s and Topol’s voices were drowned out by the feet of American cardiologists rushing to use the new agent. As they left the packed auditorium, Americans and Europeans lurched toward different corners of the ring. Today t-PA is the most widely used thrombolytic agent in the United States, whereas streptokinase is more frequently used in European countries with budgetary concerns.
Genentech became the father of an entire new American industry. Robert Swanson’s initial investment in a couple of corn beef sandwiches had a value of $46.8 billion when the Swiss pharmaceutical conglomerate Hoffmann-La Roche purchased Genentech in March 2009. By then, Genentech employed more than 11,000 people. Today as you enter South San Francisco you will encounter a road sign that proudly introduces the city as “The Birthplace of Biotechnology.”
From my ringside seat at these events, I fervently believed that at last we had the final answer for treatment of heart attack: dissolve the clot that causes it. And once again I was completely wrong. Would I never learn that on this journey, great answers create even greater questions?
Nothing in the world can take the place of persistence. Wishing will not; Talent will not; Genius will not; Education will not; Persistence is like a Genie that creates a magical force in your life.
—LUCAS REMMERSWAAL, NEW ZEALAND AUTHOR
MASON SONES’S IMAGES
of coronary arteries, which turned a giant oculus on the cause of angina, heart attack, and sudden death, triggered human intuition in ways impossible with words alone. Those images precipitated the emergence of bypass surgery and coronary care units and thrombolysis. And thus we arrive at the greatest of all spin-offs, coronary balloon angioplasty—the opening of coronary arteries using a balloon mounted on the tip of a catheter.
Like a bursting balloon, coronary angioplasty exploded our thinking, sending ideas hurtling off in every direction. Before coronary angioplasty, the cath lab was our center for the X-ray diagnosis of cardiac disease. After angioplasty, the cath lab became our hub for the treatment. The impact of balloon angioplasty is almost incalculable, because what began as a treatment for CAD spun off a fantastic spectrum of treatments for every form of structural, electrical, and heart muscle disease, and an entire new subspecialty called interventional cardiology.
The origin of angioplasty (from the Greek
angeíon,
meaning vessel or urn, and
plastos,
meaning molded) begins with radiologist Charles Dotter. We first met Dotter when he developed a method of visualizing human coronary arteries by injecting X-ray dye into the aorta, only to be trumped three months later when Mason Sones inadvertently put a catheter direct into a coronary artery. Dotter shared striking personality similarities with Walt Lillehei. He was a practical genius who skipped a grade and disassembled and rebuilt all kinds of machines in his youth. He also was an exceptional painter and photographer. He was charming, funny, flamboyant, and he cared nothing for society’s conventions. He was an incurable risk-taker. He flew an airplane. His passion was mountaineering. He set himself the goal of climbing every one of the sixty-seven peaks over 14,000 feet in the continental United States, and he did it. Every one. Like Lillehei, he, too, had radiation therapy (for Hodgkin’s disease) and ignored his disease’s lethal implication, celebrating his survival by climbing the Matterhorn at age fifty without a guide.
And, well, like Bill Mustard swallowing goldfish, Charlie was a trifle crazy. Dotter’s biographer Misty Payne tells of Charlie lecturing at an 8 a.m. department of medicine conference:
He was talking about what you could realize if you could get a catheter in the heart and what the graphs would look like. Well, he brought in a rather large—standing about six feet tall—cathode oscillograph, which is, you know, like a TV screen with these graphs on it. And he said, “I’ve been standing here and talking to you for about twenty minutes, and all this time I have had a catheter in my heart,” whereupon he rolled up his sleeve, and there was the end of the catheter. And he said, “Now I’ll show you what a normal heart reading looks like.” So he went and he plugged himself into the machine, and we were all kind of gasping, you know. There’s a man standing there with a catheter in his heart—and he moved it among the chambers of the heart as he stood there, and he explained what the graphs represented. It was an absolutely horrifying example, but it was the kind of thing he did, to say it is perfectly safe.
Within the affectionate definition of misfit that characterizes so many we meet in this history, even today I have to rank Charlie Dotter near the top. Creativity, it seems, sometimes finds a soul mate in a charismatic, show-off, unconventional, risk-taking personality.
Dotter was appointed chairman of the department of radiology at the University of Oregon at age thirty-two, the youngest in the country, and held the position for an academe-eternity: thirty-two years. When Dotter was appointed, vascular obstructions were treated by open surgery. In 1963, while performing an X-ray examination of blood vessels, Dotter accidentally completely opened a partially obstructed artery as he advanced his catheter from his patient’s leg into the aorta. With the same chance-favors-the-prepared-mind attitude as Mason Sones and Marcus DeWood, Dotter was open to discovery by serendipity. He and his fellowship trainee Melvin Judkins decided to test the idea that obstructed vessels could be opened with catheters. They developed a set of stiff catheters of progressively larger diameter. In cadavers, they started with the smallest diameter catheters then pushed one after another through the obstruction until the vessel was finally completely open. It seemed to work. They were ready to test their system in patients.
Laura Shaw was a gruff eighty-two-year-old diabetic with a nonhealing ulcer and gangrenous toes due to obstructions in the arteries in her legs. She adamantly refused to have her toes amputated by her surgeon Dr. William Krippaehne. As a last resort Krippaehne, who knew of the cadaver experiments, sent her to Dotter to see if he could reopen the obstructed leg vessel.
Dotter was lucky. Shaw’s angiogram revealed the obstruction was short, in a large diameter vessel, and was easily reached through the skin. He pushed a wire across the obstruction. Then, starting with a stiff small diameter catheter, Dotter progressively dilated the diseased vessel segment by forcing larger and larger diameter catheters through it. The response was startling. Within minutes color had returned to Laura Shaw’s foot and it was now warm. Within a week, her pain disappeared and the ulcer healed soon thereafter. Dotter performed an angiogram at three weeks and again at six months: the vessel remained open. Vinegary Laura Shaw died of congestive heart failure three years later at age eighty-five, as she never failed to remind her surgeon, “still walkin’ on my own two feet.”
As he treated patient after patient, surgeons were not enthusiastic about losing their patients to “Dottering,” as the procedure became known. So they called him “Crazy Charlie.” He had an answer. Soon every Dotter lecture included a photo of a surgeon’s written requisition for a diagnostic angiogram of the legs with the surgeon’s handwritten notation “visualize but do not try to fix.” Dotter’s angiogram showed a major and a minor vascular obstruction in the leg. Dotter dilated the major obstruction, but “did not fix” the minor one, since it was not necessary. Dotter had complied with a strict literal interpretation of the surgeon’s orders, and still saved the patient’s leg. A showman to rival Lillehei, Dotter topped off his lectures with a film on his technique which included a photograph of him and this very patient standing on the summit of 11,000-foot Mount Hood a year after the procedure.
Although Dotter opened obstructed vessels, his procedure had important limitations. His large diameter catheter left a gaping hole at the point of entry into the artery, which often required surgical repair. His rigid catheters sent torn-off chunks of atheroma cascading downstream to completely reobstruct smaller vessels. So, while Charlie Dotter proved that obstructed vessels could be opened by a distending force from within, the toxic mixture of his brash style and the strong opposition from surgeons doomed his method in the United States.
Europeans were not so hidebound. After seeing Dotter’s technique described at a radiology symposium Dr. Andreas Gruentzig, a completely unknown young radiologist in Zürich, Switzerland, was inspired to think outside the box. Gruentzig’s vision was that he could improve Dotter’s technique, and then apply it to CAD, that he could treat heart disease with a catheter instead of cracking open the chest. Gruentzig’s story of persistence in the face of repeated failure and rejection is the most inspiring in our half-century chronicle of cardiology, and stands as a message for each of us regardless of our occupation or circumstance.
* * *
ANDREAS GRUENTZIG WAS
born in Dresden, an East German city near the Polish border, in 1940, during the period between the Nazi invasion of Poland and the entry of the United States into World War II. Five years later, on the evening of February 13, 1945, Allied firebombs reduced the “Florence on the Elbe” to rubble, killing 135,000 people. It was the single most destructive bombing of the war, more so than Hiroshima or Nagasaki. The firebombing of Dresden was particularly tragic because the city had no strategic value at a moment when the Germans were on the verge of surrender. Before the bombing, his parents had moved the family to Rochlitz, a small town about fifty miles west, only to have their new home commandeered by Allied forces as a headquarters. Andreas’s father was later lost during the battle for Berlin. Fatherless and impoverished, Andreas had to fend for himself in the early postwar years. His deliverance from poverty came through the classroom. At age seventeen Andreas escaped from East Germany to be taken in by his older brother in Heidelberg. Poor but focused by ambition, the immigrant kid graduated from medical school seven years later, chose radiology, and was accepted for training in Zürich. When he saw the Dotter procedure, Andreas cajoled his boss to allow him to travel to Nuremberg, Germany, to learn the procedure.
When he returned from Nuremberg to Zürich in 1970 Gruentzig performed Dotter angioplasty on a modest number of patients. But his boss in radiology came to feel that Gruentzig’s puttering was not only taking him from assigned work, but also creating complications when an occasional dislodged atheroma created a surgical emergency. It was a now-familiar story: where Gruentzig saw opportunity, his boss saw complications. But Gruentzig had an intuition. In his mind’s eye Gruentzig imagined that a forcefully expanded balloon pressed against the narrowed segment might dilate it without snowplowing off the atheroma like Dotter’s catheters. That single idea became his life’s obsession. He thought of it, dreamed it, lived it every moment of the day. As he had so many times before in his life, Gruentzig found an escape route: he maneuvered a transfer into the department of cardiology. Now his target would be the coronary arteries.
