The Heart Healers (41 page)

But still, the extraction was colossally inefficient, requiring many gallons of juice to produce an amount of brown powder that barely covered a fingernail. That final critical step, an efficient method for extracting penicillin from mold juice, was designed by Florey’s lowly graduate PhD student Norman Heatley. Mass production of penicillin began soon after the bombing of Pearl Harbor. Where Fleming’s single laboratory could not succeed, the collaboration of thousands of people and thirty-five institutions including universities, government agencies, research foundations, and pharmaceutical companies did. By D-day in 1944 the Allies had sufficient supplies of penicillin to treat all wounded forces, saving countless lives.

Fleming was characteristically humble about his role in one of medicine’s greatest discoveries, describing it as the “Fleming Myth.” He never failed to laud Florey and Chain for transporting penicillin from his dream to mankind’s reality. “I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic … But I suppose that was exactly what I did,” he mused. Fleming, Florey, and Chain received the Nobel Prize in Physiology and Medicine in 1945. But for me, the graduate student Norman Heatley stands as a metaphor for all my young physician-scientist mentees who are sometimes unrecognized contributors to the work of their mentor. As Sir Henry Harris, who succeeded Howard Florey as head of the Dunn School at Oxford, observed, “Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin.”

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WHEN SANKYO ABANDONED
him, only one person still believed Akira Endo had discovered an important drug. When Endo presented his research two years earlier at the lipid symposium in Philadelphia, physician scientist Roy Vagelos, a brilliant son of poor Greek immigrants, had just been installed as the new president of Merck pharmaceuticals. Vagelos had excelled everywhere, from college at the University of Pennsylvania, to medical school at Columbia, residency at Massachusetts General Hospital, and research at the National Institutes of Health before becoming chair of the department of biochemistry at Washington University in St. Louis. In his new job at Merck, Vagelos deeply wanted a signature blockbuster drug. CAD was the nation’s number one killer. Vagelos knew each step in cholesterol synthesis and he saw that Endo might have found a way to block the most critical one.

After Endo’s 1976 oral presentation in Philadelphia, later in Tokyo Merck and Sankyo signed a one-page disclosure agreement granting Merck access to Endo’s methods and results. From Sankyo’s perspective it was a trivial document. They were discontinuing their research on mevastatin, and if Merck somehow discovered a way to use the drug, Sankyo held the patent. The paper was as worthless as Endo’s research.

But history suggests that perhaps there should have been a second page. The agreement failed to protect Sankyo’s interest if Merck discovered a different member of the statin family using Endo’s methodology. And that was precisely what Vagelos intended to do.

Two years later Merck had succeeded in creating a new system for testing thousands of soil extracts for the elusive cholesterol synthesis inhibitor. In November 1978 as Endo packed his boxes to leave Sankyo, Merck’s statin program brought in the gusher. Prepared to test thousands of samples, Merck had discovered a cholesterol synthesis inhibitor in its very first week of testing. Merck called their drug lovastatin. They initiated testing in normal volunteers; lovastatin reduced blood cholesterol with few short-term side effects. But in 1980, Sankyo’s animal lab reported that high-dose mevastatin induced intestinal lymphomas in dogs. When Merck learned that Sankyo had terminated their clinical trial because statins caused lymphomas in dogs, Vagelos felt he had to follow suit. He could hardly continue testing a drug in patients if it was known to cause cancer in animals. Cardiology’s blockbuster drug was headed to the dustbin of history. Statins were twice dead.

Sometimes a man and an era, like Churchill and World War II, are made for each other. So it was with Vagelos and statins. Hardheaded Roy Vagelos had to see for himself. Vagelos and newly hired research director Edward Scolnick designed their own comprehensive animal laboratory toxicity studies. That decision changed the course of history. The lymphomas reported by Sankyo’s investigators turned out to be scientific error. The “tumors” were due to massive doses of the statins. There were no tumors. None at all.

American leaders in lipidology had been searching for a drug that lowered cholesterol. Their first drug, cholestyramine, the source of so many academic insults, was not the answer. It had proven to be impotent and patient-unfriendly. With strong support of physician advocates, Merck was allowed to resume safety and efficacy testing in patients. In November 1986 Merck sent a van from Philadelphia to Washington, where it plopped 104 volumes at the feet of the FDA, to support their claim that their new statin was safe and effective for lowering blood cholesterol. Following a recommendation for approval by its advisory panel, the FDA approved the drug in August 1987, with what may rank as their all-time least-enthusiastic approval. The FDA allowed marketing with the caveat that Merck stipulate that although the drug lowered cholesterol, it had no proven clinical benefit. By now, eleven years had elapsed since Endo’s landmark discovery.

Merck finally had its foot in the door. A second more potent cousin of lovastatin, called simvastatin (Zocor) was now ready for testing. Merck initiated a five-year clinical trial. In April 1994, a full eighteen years after Endo’s discovery, investigators announced the results of the Scandinavian Simvastatin Survival Study using simvastatin in heart disease patients with elevated blood cholesterol. During five years of follow-up the treated patients had a 35% reduction in their cholesterol, and an astonishing 42% reduction in heart attacks compared to placebo.

For practical purposes, the San Andreas Fault of cardiology disappeared that day. No longer did bitter camps confront each other across the cholesterol divide. The argument was over. The following year, Merck sold over $1 billion of Zocor.

It was just a single number: 42%. But it precipitated a final great paradigm shift, a complete change in our worldview. It had popped up suddenly like the first mountain flower of spring on a desolate landscape. The new fantastic idea, both simple and profound, is: CAD is a preventable disease. The idea dominates today’s thinking.

And the Rest of the Story? In 1994 Akira Endo went to see his doctor. Endo’s blood total cholesterol was 240 mg/dl, and his LDL cholesterol was 155 mg/dl. “Don’t worry, we have very good drugs to lower your cholesterol,” his doctor assured him, not knowing that he spoke to the discoverer of statins.

Endo, however, was not forgotten by the scientific community. In 2008 he received the Lasker Award for his labors in a warren next to a south Tokyo train station. The Lasker Award is one of the world’s most respected science awards, recognizing those who have made major advances in the understanding, diagnosis, and treatment of human disease. Eighty-three Lasker laureates have received the Nobel Prize, over thirty in the last twenty years. There is still time for Endo.

As Endo received the Lasker award it was too late for vindication of Russian Nicolai Anitschkov, the father of the lipid hypothesis. He had been brought down by the disease he defined, dying of a heart attack on Pearl Harbor Day in 1964. How renowned would he be today had he been born in a different place, in a different world environment? Author Daniel Steinberg muses, “If the full significance of his findings had been appreciated at the time, we might have saved more than 30 years in the long struggle to settle the cholesterol controversy and Anitschkov might have won a Nobel Prize.”

In the ensuing chapters, we will begin to imagine strategies to save ourselves, our family members, and our patients with hearts too good to die. And yet, let’s pause a moment to recall that but for a nonconformist Japanese and a bullheaded Greek, it seems likely that the word “statin” would never have entered our vocabulary.

24

YOSEMITE

Wake up, O sleeper, rise from the dead, and Christ will shine on you.

—EPHESIANS 5:14

LET’S SEE HOW
everything we learned during those intervening years came to bear on Greta Adams’s life. When Greta’s heart fibrillated, Jon reacted instantly. “V fib” he shouted and at the same time, like a judge calling for order, slammed the gloved fist of his right hand down hard in the middle of Greta’s sternum. Called “the chest thump,” this is the first step in treatment of ventricular fibrillation because it induces a weak electric shock to the heart. Rarely the thump will restart a heart in ventricular fibrillation. But above Greta the monitor stayed silent. The electrocardiogram showed ventricular fibrillation and arterial blood pressure was zero, meaning no blood was being pumped to the rest of Greta’s body. Jon initiated CPR. Four minutes without blood flow would mean irreversible brain damage and death. Jon was on the clock.

Cupping one hand behind the other and delivering the weight of his body through his shoulders, Jon began rhythmically depressing the middle of Greta’s chest. Each thrust depressed her sternum about two inches. Greta’s left ventricle was squashed against her vertebrae at a rate of once per second, causing ejection of sufficient blood into the aorta to maintain life. Behind him the lab erupted into controlled frenzy. Well-drilled for emergencies, each person in the lab took action: a terse “Code Blue, two” into a wall phone, a rolling crash cart, syringes filling, lubricating gel on paddles, a defibrillator “arming” to deliver 400 joules of energy. The defibrillator appeared at Jon’s side. Jon grabbed its two paddles, pressed one high on Greta’s right chest and the other on her left chest below the heart. “Clear!” he shouted, to be sure no one was in direct contact with Greta as the electric jolt went through her. Her body convulsed, then fell back. “Still v fib,” Jon shouted. While a technician took over pumping on the chest Jon injected cardiac stimulants through the catheter in Greta’s heart and repeated the shock. Still v fib.

An anesthesiologist crashed through the cath lab’s double doors. Standing at the head of the cath table, he bent Greta’s head back to straighten her trachea (windpipe). Holding open her mouth with his left hand, he inserted an illuminated blade called a laryngoscope into her mouth, then advanced it forward until he could see the vocal cords. He squinted through his narrow field of view, ignoring the bouncing created by the rhythmic pumping on Greta’s chest.

“Hold a couple of beats,” he said, and at the instant the bouncing stopped he pushed a flexible airway tube past the cords.

“OK to resume,” he said after several seconds. He attached a compressible airway bag to the tube and began rhythmic expansion of Greta’s lungs. The Code Blue team was now a surrogate for Greta’s heart and lung function.

Another try at defibrillation, another failure. Jon grabbed a coronary stent, reasoning that perhaps Greta’s left coronary artery obstruction had closed completely. If that was the cause of her sudden death, a stent inserted across the obstruction might open a floodgate of oxygenated blood to her heart. He had never placed a stent in a dead person with a nonbeating heart. It was an experience he hoped never to repeat. As the pumping on Greta’s chest bounced her limp body on the table, Jon struggled to maneuver a collapsed stent into Greta’s left anterior descending coronary artery until it straddled the obstruction. He inflated a balloon within the stent. The obstruction, crushed into the wall of the blood vessel, disappeared. Later when I reviewed the angiographic images with Jon, I was awed by his technical skill, and the transient eerie image of his technician’s hands pressing rhythmically on Greta’s chest wall, above her lifeless nonbeating, fibrillating heart.

Jon repeated the cardiac drugs and repeated the defibrillation shock. No effect. Medical cardiology was out of options. For Greta Adams the words of Pope Paul VI now seemed prophetic, “Whatever you want to do, do it now. There are only so many tomorrows.” At that moment, it seemed there were no more tomorrows.

Jon had one last arrow in his quiver. Jon reached back to where modern cardiovascular medicine first took root. He called a cardiac surgeon.

“Can you put her on heart-lung bypass?”

“Jon, drop her body temp with a cooling blanket, to diminish her brain’s need for oxygen. I’ll see you in the OR. But even on the machine, there’s only a tiny chance we can get her heart to restart when you can’t” was the reply.

Greta’s expert team performed consummately coordinated CPR (cardiopulmonary resuscitation). One cath lab technician pumped on her chest sixty times a minute while the anesthesiologist forced air into her lungs, and Jon and his crew lifted Greta’s inert body off the cath table, onto a gurney, out of the lab, and raced down the hall to the surgical suite. As soon as they entered, the surgery team focused on connecting a complex system of tubes to Greta’s arteries and veins as Jon’s crew continued CPR. Greta was being connected to a modern version of John Gibbon’s heart-lung machine.

By the time the cardiac surgeon stripped off his mask, Jon and his crew had been manually pumping on Greta’s chest for two hours. Neither Jon nor I have ever seen a patient survive without brain damage from this duration of cardiopulmonary resuscitation. In fact, because the chances of recovery are vanishingly small, manual cardiopulmonary resuscitation is rarely continued for two hours.

Jon, emotionally drained, could barely face his next task. He called the hospital chaplain and went to discuss the grim news with Tyler Adams. He could only wait until tomorrow, hoping for a miraculous recovery of heartbeat. Yet even if Greta’s heartbeat returned, no one could say whether her brain had survived the cardiac arrest and the brief interruptions of pumping when the tube was inserted into her airway, the stent was placed in her left coronary artery, and she was moved to the surgical suite. Recalling the success of body cooling for preserving brain function in the early days of cardiac surgery, he could only hope that cooling might also be part of Greta’s salvation. As she exited the surgical suite, Greta was neither clearly dead, nor clearly alive. She was suspended in cardiac purgatory.