Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (28 page)

Einthoven's astonishment must have been due, as Levine supposed, to the fact that he was unaware, like many others in Europe, of the developments in the United States concerning the clinical and electrocardiographic diagnosis of myocardial infarction.

Sharing the Prize

One event that occurred after Einthoven received the Nobel Prize in Physiology or Medicine in 1924 speaks volumes about his integrity. In the construction of his string galvanometer and laboratory experiments over many years, Einthoven was rather clumsy with his hands and relied very much on the collaboration of his chief assistant K. F. L. van der Woerdt. Years later, when he received the $40,000 in Nobel Prize money, Einthoven wished to share it with his assistant but soon learned that the man had died. He sought out the man's two surviving sisters, who were living in genteel poverty in a kind of almshouse. He journeyed there by train and gave them half of the award money.

Einthoven spoke in a jocular manner of his string galvanometer: “Do I not read all the secrets of the heart?”

In 1926 the Cambridge Scientific Instrument Company introduced the first truly portable ECG, an eighty-pound machine requiring wheeled trolleys. Today, small electronic ECG monitors are ubiquitous in physicians’ offices and hospital coronary care and intensive care units and surgical suites.

In time, however, it became increasingly clear that Einthoven's electrocardiograph did not truly reveal “all the secrets of the heart,” and medical conquistadors arose with a more aggressive approach to directly probe the heart itself.

23

What a Catheter Can Do

A twenty-five-year-old surgical intern in Germany, Werner Forssmann, famously performed the first human cardiac catheterization in 1929—on himself!—in an astounding example of self-experimentation in medicine.

In medical school, Forssmann had been inspired by a study undertaken by two French physiologists decades earlier, in 1861. Étienne Marey and Auguste Chauveau had inserted a thin tube into the jugular vein of a conscious, standing horse and guided it into its heart, from which they recorded pressure readings of the heart's chambers. This pioneering procedure was accomplished without disturbing the horse's heart. The print from an old engraving depicting the event had captured Forssmann's imagination. “I hoped that it should be possible to transfer this procedure to man.”

Forssmann received his medical degree from the University of Berlin in 1929. That year, he interned at a small hospital northwest of Berlin, the Auguste-Viktoria-Heim in Eberswalde. He pleaded with his superiors for approval to try a new procedure—to inject drugs directly into the heart—but was unable to persuade them of his new concept's validity. Undaunted, Forssmann proceeded on his own. His goal was to improve upon the administration of drugs into the central circulation during emergency operations.

The circumstances of the incident on November 5, 1929, revealed by Forssmann in his autobiography, could hardly have been
more dramatic. The account reflects Forssmann's dogged determination, willpower, and extraordinary courage. He gained the trust of the surgical nurse who provided access to the necessary instruments. So carried away by Forssmann's vision, she volunteered herself to undergo the experiment. Pretending to go along with her, Forssmann strapped her down to the table in a small operating room while his colleagues took their afternoon naps. When she wasn't looking, he anesthetized his own left elbow crease. Once the local anesthetic took effect, Forssmann quickly performed a surgical cutdown to expose his vein and boldly manipulated a flexible ureteral catheter 30 cm toward his heart. This thin sterile rubber tubing used by urologists to drain urine from the kidney was 65 cm long (about 26 inches). He then released the angry nurse.

They walked down two flights of stairs to the X-ray department, where he fearlessly advanced the catheter into the upper chamber (atrium) on the right side of his heart, following its course on a fluoroscopic screen with the aid of a mirror held by the nurse. (Fluoroscopy is an X-ray technique whereby movement of a body organ, an introduced dye, or a catheter within the body can be followed in real time.) He documented his experiment with an X-ray film. Forssmann was oblivious to the danger of abnormal, potentially fatal heart rhythms that can be provoked when anything touches the sensitive endocardium, the inside lining of the heart chambers.

There are two conflicting accounts of the responses of his fellow staff members. Forssmann's version was: “News spread like wildfire in a hospital. Suddenly [a fellow intern] burst in [to the X-ray room], half asleep and his hair all tousled: ‘You idiot, what the hell are you doing?’ He was so desperate he almost tried to pull the catheter out of my arm. I had to give him a few kicks in the shin to calm him down.”
¹

Quite another version was offered by another colleague intern, who claims that he heard a rumor that Forssmann had just committed suicide by pushing a catheter through a vein and into his heart. Bursting into Forssmann's room, he found him silent and pale, staring at the ceiling, with the bedsheets soaked in blood and the catheter still in his arm. The catheter was pulled out, but Forssmann refused to divulge if his intentions were suicidal or investigational. In his colleague's experience,
Forssmann was always “a rather queer, peculiar person, lone and desolate, hardly ever mingling with his co-workers socially. One never knew whether he was thinking or mentally deficient.”
²

Forssmann's report in the leading German medical journal garnered him not hosannas but instead fierce professional criticism and scorn. In response to a senior physician who claimed undocumented priority for the procedure, the twenty-five-year-old Forssmann was forced to provide an addendum to his publication one month later. Rigid dogmatism and an authoritarian hierarchy characterized the German medicine of that day. The human heart, as the center of life, was considered inviolable by instrumentation and surgery.

Forssmann's surgical career was subsequently severely curtailed. Nevertheless, he continued his experimental pursuits with injection of X-ray dyes through a catheter into dogs and his own body. Since hospitals at that time did not have special quarters for experimental animals, Forssmann's mother cared for the dogs in her apartment. Forssmann would inject a dog with morphine, put the sleepy animal in a potato sack, and take it by motorcycle to the hospital. As in the experiments by the French physiologists, Forssmann would insert a catheter through a vein in the dog's neck and into its heart. He would then inject dyes and attempt X-ray documentation.

Forssmann had assured himself of the safety of the iodine-containing contrast solution in humans by pressing it against the lining of the inside of his mouth for several hours, without reaction. On subsequent experiments on himself, the catheter course did not always oblige his intentions. On the first attempt, the catheter tip deflected into a neck vein rather than toward the heart. When the contrast dye was injected after proper positioning of the catheter, he felt only a mild irritation of the nasal membranes, an unpleasant taste in his mouth, and a transient dizziness. When he presented the tentative results of his studies—on repeated successful passages of a catheter into the heart chamber in both dogs and himself—at the annual meeting of the German surgical society in Munich in April 1931,
³
he received an icy response. There was no applause and no discussion. It was said that Forssmann stopped his self-experimentation only when he had used all of his veins with seventeen cutdowns.

It was not Forssmann but two New York physicians, André Cournand and Dickinson Richards, a few years later, who advanced cardiac catheterization in humans in 1940 at Bellevue Hospital. Cournand readily acknowledged Forssmann's explorations and, years later, contributed the preface to Forssmann's autobiography. He described Forssmann as “not lacking in pride of self, a man at once disputatious, full of resources and will power, and endowed with physical courage, if not with great political perspicacity.”

In 1956 the Nobel committee announced it would award that year's prize for Medicine to Forssmann, Cournand, and Richards. Plucked out of obscurity a quarter century after his exploits and told of the news, Forssmann, now a country doctor in the Black Forest, told a reporter, “I feel like a village parson who has just learned that he had been made bishop.” Cournand stated in his Nobel lecture that “the cardiac catheter was… the key in the lock.”
⁴
With the presentation to Forssmann, it was stated that he had been “subjected to criticism of such exaggerated severity… based on an unsubstantiated belief in the danger of intervention, thus affording proof that—even in our enlightened times—a valuable suggestion may remain unexploited on the grounds of a preconceived opinion.”
⁵

A Milestone in Visualization

To fulfill the demands put forward by the new surgeries for congenital heart defects, the next imperative associated with cardiac catheterization in the 1950s was the need to develop a procedure known as “selective angiocardiography.” This procedure involves the injection through the catheter of a radiopaque substance, or “contrast medium” (loosely termed “dye” by some), into the heart or aorta to enable visualization of the heart's interior and abnormalities of the aorta. A safe, reliable technique for entrance into the arterial system was essential. At the time, a surgical cut-down was the most widely used method of introducing a catheter into an artery or vein before guiding it to the desired location and injecting contrast medium.

This problem was ingeniously solved by a thirty-two-year-old radiologist, Sven-Ivar Seldinger, of the Karolinska Institutet of Stockholm. He devised a method to introduce a catheter into the vascular system (usually within the groin) through the skin without the need for a surgical incision to expose a vessel. The procedure is simpler, safer, and has little risk of complication.

Using Seldinger's technique and the intravascular injection of a contrast medium, doctors can see not only the position and course of a vessel but especially the presence, degree, and localization of atherosclerotic obstructions. Seldinger's concise nine-page report in the prestigious Swedish journal
Acta Radiologica
in 1953 established a medical milestone.
⁶

Seldinger's technique can be likened to Harvey's discovery of the circulation of blood—an explosive illumination that enabled vast advances. It became widely adopted for catheterizations of the vascular system and led to modern cardiology and cardiovascular surgery.

T
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As the great vessel, the aorta, carries the richly oxygenated blood from the contracting left ventricle of the heart, its immediate first branches nourish the heart muscle itself. These branches, likened to a crown (
corona
in Latin) as they arise from just above the heart, are named the coronary arteries. Doctors very much wanted to be able to see inside the aorta to look for leaking valves, blockages, and other abnormalities.

Investigators never dared to directly enter the openings of the coronary arteries with a catheter and introduce contrast material to enable their visualization by X-rays. This fear was based on two perceived calamitous effects that would deprive the heart muscle of oxygen: spasm of the coronary artery induced by the catheter and replacement of its blood by an unoxygenated iodine-containing contrast fluid. A host of indirect methods were attempted at numerous research centers
over several years, but no investigator would attempt to selectively catheterize a coronary artery in a human. Instead, the tip of the catheter was often placed within the thoracic aorta as close as possible to the openings of the coronary arteries to deliver the contrast fluid.

Then, in 1959, a brief abstract appeared in the journal
Circulation.
⁷
It was based on an oral presentation at the annual meeting of the American College of Cardiology by F. Mason Sones Jr. and associates from the Cleveland Clinic. Its opening sentence declared that “a safe and dependable method has been devised for contrast visualization of the coronary arteries to objectively demonstrate atherosclerotic vessels.” What stirred only a ripple of interest at the time was shortly recognized as a landmark achievement. Now the location, number, and severity of blockages of the coronary arteries could be identified. This would advance cardiology as much as the electrocardiograph had done half a century earlier.

Today, coronary artery disease is the number one killer in the Western world. In the United States, about 17 percent of the adult population has some cardiovascular condition. Each year, 650,000 Americans suffer a first heart attack. About 450,000 have a recurrent attack. Heart disease occurs because cholesterol-containing plaque accumulates in the walls of the coronary arteries and eventually becomes a blockage that prevents blood from reaching cells. “Atherosclerosis” is the term used for the deposits of fatty plaques on the walls of arteries.

How Sones's method had been “devised,” however, was not openly acknowledged until many years later, after the technique had been universally adopted in the revolutionary advance of reconstructive coronary surgery.

Mason Sones, a pediatric cardiologist, had been recruited to the Cleveland Clinic nine years earlier to start a cardiac catheterization laboratory, having learned the technique at the Henry Ford Hospital in Detroit. Complementing cardiac catheterization with angiocardiography, his work initially involved congenital heart disorders in children and rheumatic heart disease in adults. Sones was a perfectionist who worked prodigiously. His frequent comment about his own work was “it's not good enough.”