WUSTL

Washington People: Igor Efimov

Biomedical engineer works to restore the heart’s rhythm
By Diana Lutz

David Kilper/WUSTL

Igor Efimov, PhD (right), the Lucy & Stanley Lopata Distinguished Professor of Biomedical Engineering, and student Jacob Laughner work with a chamber used to study heart tissue treated with voltage-sensitive dyes that fluoresce with an intensity proportional to the transmembrane electrical potential of cardiac cells, allowing the scientists to map waves of electrical impulses as they travel through the heart.

 

More than 5 million Americans struggle with atrial fibrillation, a dangerous heart condition that can increase the risk of stroke and heart deterioration. While ventricular fibrillation can be treated successfully with implantable defibrillators, similar shock treatments for atrial fibrillation are intolerable for patients. Many say the atrial defibrillation is so painful that they would rather live with the risk of death than be shocked again.

Igor Efimov, PhD, the Lucy & Stanley Lopata Distinguished Professor of Biomedical Engineering in the School of Engineering & Applied Science, and a member of the Washington University in St. Louis community since 2004, is working to resolve that quandary. He and his research team are developing an implantable atrial defibrillator that restores the heart’s rhythm with low-energy shocks, an innovation that will make defibrillation relatively painless.

“Efimov is just amazing,” says Richard Schuessler, PhD, research professor of surgery at the Washington University School of Medicine in St. Louis and longtime colleague. “(He is) one of the most creative people I know. Sometimes I’m actually afraid to talk to him because I’ll start off and all of a sudden he’ll say, ‘oh, oh, oh, did you see this article in Science, or ‘I’ve been talking to this guy and ...’ He is always bubbling with ideas.”

Childhood in Siberia

For Efimov, the journey to a major research institution in the heart of America began in the much cooler Siberian hinterlands of the Soviet Union. He grew up in a secret town in Siberia called Krashnoyarsk-26.

Stalin decreed the town be built after Winston Churchill’s Iron Curtain speech in 1946. The speech put Stalin on notice that the Soviet Union and the West, allies during the war, were now on hostile terms.

The people of Krashnoyarsk-26 processed plutonium and built spy satellites.

“My hometown was created by Stalin’s decree,” Efimov says, “and so was my alma mater, the Moscow Institute of Physics and Technology, whose creation was another side effect of Churchill’s Iron Curtain speech.

Efimov earned a master’s degree in experimental nuclear physics at the Institute.

“After I got my degree,” he says, “I typed my last name in PubMed and I got hits on papers in elementary particle physics that had hundreds of authors. I realized that I would be part of such huge teams it would be difficult to make a personal contribution. So I decided to go into biology instead,” he says.

He had never supposed he might emigrate. Not only had he grown up in a secret town, he had been trained in control theory relevant to intercontinental ballistic missile systems guidance in exchange for exemption from the draft. “I never thought they’d let me leave,“ he says.

But in 1991 there was a putsch in Russia, and that changed everything. “I defended my dissertation on Christmas Day, 1991,” Efimov says. “After that it had to go to some state agency for ratification, which arrived in March 1992. A month or two later Yeltsin disbanded the KGB and opened the borders.”

“I immediately started applying for postdoctral postions in the United States and Europe,” Efimov says.

“I took the first position I was offered,” he says, “and we left with two suitcases and all my savings, which was 800 rubles. At the exchange rate of the time, they were worth six or seven dollars.” He bought the airline tickets with money from a revolving slush fund set up by recent Russian expatriates to help other Russians.

After appointments at several other universities, he arrived at WUSTL in 2004. He also has secondary appointments in cell biology, physiology, radiology and medicine in the School of Medicine.

The heart: a highly complex electrical device

Efimov’s research specialty is disturbances of cardiac rhythm known as arrhythmias, a term that includes a large number of very different conditions.

One of the most frightening, however, is ventricular fibrillation, or V-fib, in which the muscle in the major pumping chambers of the heart quiver uselessly instead of pumping rhythmically.

How could this happen? The answer hinges on the fact that cardiac muscle cells have the ability, usually reserved for nerve cells, to initiate an action potential, or traveling wave of electrical activity, on their own.

While this ability is normally suppressed, when something goes wrong, it can lead to electrical impulses that race around and around the heart instead of moving from one end of the heart to the other and then stopping. When an entire chamber of the heart is involved in these “re-entry circuits,” it quivers chaotically and is said to be fibrillating.

Because this is not simple behavior Efimov is understandably skeptical that it will yield to simple treatments.

Reductionism never gets there from here

In an editorial in a recent issue of Circulation Research, he remarks that cardiac physiology has long been seduced by reductionism, the idea that a system can be understood by understanding its parts.

He dates the shift toward reductionism to 1952, when Alan Lloyd Hodgkin and Andrew Huxley described action potentials in the squid giant axon.

Drilling down, cardiovascular physiologists focussed on the heart, then heart tissue, than myocytes, then ion channels in myocytes.

But, Efimov says, the simpler things got, the more complex they became. Ion channels have many isoforms and subunits, and unexpected auxiliary proteins. They are also part of complex signaling pathways activated by a diverse array of electric and mechanical stimuli.

Worse, therapies based on this reductive approach consistently haven’t panned out.

“I believe it is becoming obvious to pretty much everyone in the field that we have to move toward integration now,” Efimov says. “We have to take all this knowledge and create a systemic, holistic understanding of the heart if we are going to deliver on our promises.”

This is the lodestar by which he tries to chart the course for his laboratory.

One of his innovations is to study cardiovascular problems in human hearts rather than in the hearts of mice, the most popular animal model in cardiophysiology.

He has established connections with local institutions that supply his lab with human hearts. The hearts are either diseased ones removed from patients undergoing heart transplants or “non-failing” hearts that have been donated for research but are considered unsuitable for transplantation.

Using voltage-sensitive dyes his lab creates maps in which invisible waves of electrical potentials sweeping across the heart’s chambers are rendered as vibrantly visible waves of color.

Although the program is only three years old, the work has already demonstrated that human hearts are quite different from those of mice. (See “New study calls into question reliance on animal models in cardiovascular research.”)

Maria Efimov

(From left) Igor Efimov, with his daughter Maria; wife Tatiana, a molecular biologist; and son Andrew.

Another target of Efimov’s research is atrial fibrillation. Again Efimov has looked for a therapy that treats the whole heart, not just its parts.

Ventricular defibrillators have been implanted in patients for 30 years, and clinical studies show they save lives. But patients with atrial fibrillation are conscious when their hearts are shocked and the shocks are painful beyond endurance.

Efimov’s team has devised a painless implantable defibrillator that “unpins” destructive electric circuits in the heart by delivering low-energy shocks to their “anchor points.”

He has founded a company called CardiaLen to develop the defibrillator and if everything goes as planned, the defibrillator will enter stage I clinical trials in about a year.

“If I could find a way to pay for it I would quit my job and go be a post-doc in his lab,” Schuessler says. 

Fast facts about Igor Efimov

In his suitcases brought from Russia: Clothes, but also pots and pans. At the time, he says, Russians were under the impression they had to bring dishes, pots and pans when emigrating.
Where he first celebrated Christmas: Fermilab in Batavia, Ill. The Russian expatriate community there throws a proper Russian Christmas, complete with Ded Moroz and Snegurochka.
Favorite meal: Borscht. How predictable is that, he says, adding that borscht is actually Ukrainian but his wife is Ukrainian and she does it perfectly.
Strangest treatment for heart disease encounterd: In the 1950s, some doctors would open the patient’s chest, scratch the heart with a file and staunch the bleeding with asbestos powder. “Unfortunately it didn’t work very well,” he says.
Service to Russian community: Columnist for Russian newspaper Gzt.ru, the online version of the Moscow newspaper Gazeta; member of the board of directors of russiandoctors.org, which sponsors medical missions; and president of the Russian American Science Association, which encourages peer-reviewed research on the Western model in Russia.

 

MEDIA CONTACTS
Diana Lutz
Senior Science Editor
(314) 935-5272
dlutz@wustl.edu
EXPERTS @ WUSTL
Igor Efimov
Lucy & Stanley Lopata Distinguished Professor of Biomedical Engineering
(314) 935-8612
igor@wustl.edu
Efimov Illustrated
Ironically much of Efimov's life as a young Russian was framed by what an Englishman said in rural America. Efimov attributes both the construction of his hometown and the establishment of the Institute he attended to Stalin's alarm over Churchill’s speech in Fulton, Mo., ringing the Iron Curtain down over Eastern Europe.
Efimov grew up in a secret town in Siberia called Krashnoyarsk-26 that was established after Churchill’s Iron Curtain Speech. “If you took a map of the Soviet Union and folded it in half, Krashnoyarsk was literally in the middle,” Efimov says. "It was surrounded by three rings of barbed wire — not to keep us in, but to keep others out. I call it the first gated community,” he says.
The original purpose of Krashnoyarsk-26, the secret town where Efimov grew up, was to produce weapons-grade plutonium. Here workers pose with a nuclear reactor. Efimov still worries a little about his exposure to radiation. Heat maps show that radioactive waste dumped into the nearby Siberian river, the Yenisay, can be tracked 500 miles downstream. He found that out by Googling a Norwegian site called Bellona that tracks nuclear towns and projects.
Late, factories in Krashnoyarsk-26, Efimov's hometown, built spy satellites as well.
In Efimov’s hometown, summer camp for kids was a month studying calculus and molecular biology. Not surprisingly many of the kids who attended camp became scientists. Efimov is in front on the right.
Efimov attended the elite Moscow Institute of Physics and Technology. The Institute was the brainchild of the illustrious Peter Kapitza (left), a Russian physicist who had become a professor at Cambridge University in the United Kingdom but was forcibly detained by Stalin when he returned to the Soviet Union in 1934 to visit his mother. When the British government asked for his return, Stalin replied, “Send me Rutherford and then we will send Kapitza back to England.” Needless to say Rutherford stayed in England and Kapitza stayed in Russia. Kapitza is famous for having the nerve to write to Stalin, who never replied to his letters, but, when he stopped writing, demanded to know why. In one of these letters, Kapitza urged Stalin to create an educational institution on the model of Cambridge or Massachusetts Institute of Technology but the proposal lay fallow until five days after Churchill's Iron Curtain speech, when it was abruptly approved.
Efimov has never forgotten the collapse of a widely accepted treatment for heart disease when he was a graduate student. “At the time, the preferred treatment for sudden cardiac death was something called EP-guided antiarrhythmic drug therapy (EPG),” he says. “The belief was that we would identify every mutation responsible for arrhythmia, and we would design a drug that would bind to each target and restore proper function.” To determine which drug was best, a patient was anesthetized, arrhythmia induced by shocking the heart and anti-arrhythmic drugs tested until the patient responded. Then came the MUSTT trial, a clinical trial whose results were published in 1999. “Guess what happened?,“ Efimov says. “Mortality in the EPG group was higher than in the placebo group. Only defibrillators really helped. After MUSTT, trial after trial showed that drugs that had been prescribed for years as life-saving anti-arrhythmic drugs didn’t work. In fact they sometimes increased mortality.”
While Efimov was earning advanced degrees in experimental nuclear physics and biophysics, there was considerable churn at the top levels of Soviet leadership.
The Soviet Union fell apart in 1991 and Efimov, and his wife took advantage of the loss of control to leave the country. Today, Googling his hometown from America, he discovered that it still doesn't show up on Google Maps (top) although a small city shows up on Google Earth (bottom). “My town is still secret,” he jokes.
Efimov's first job in America was as a postdoctoral researcher in Guy Salama's lab at the University of Pittsburgh, where he learned an optical technique for visualizing electrical activity in the heart with voltage-sensitive dyes that he still uses in his laboratory.
When he has an opportunity, Efimov studies the hearts of black bears, 13-striped ground squirrels and the Siberian ground squirrel shown here. Unlike most mammals, which go into cardiac arrest when their body temperature drops too low, true hibernators maintain their heart rhythm even when their body temperature is close to 0 degrees Celsius.
Efimov is a keen student of the history of his field. The first person to be revived by electric shock was a three-year-old girl when knocked herself unconscious in 1788 and was shocked back to life by a Mr. Squires of London using a generator and a Leyden jar. This 1792 report in the Gentlemen's Magazine describes the first defibrillator, devised by a Mr. Fell. Efimov's colleague His colleague Richard Schuessler says he always includes a few history slides in his talks if he knows Efimov will be in the audience.
In part because of his knowledge of the history of his field, Efimov is skeptical of theories that reduce the body (or the heart)  to an assemblage of components, as satirized in this poster. He feels an synthetic, holistic understanding is more likely to produce the successful therapies research scientists have long promised patients.