To Prevent High Mortality, It Is Necessary To Recreate the Fundamental Cardiological Science

15:04, December 28, 2018

Ural Federal University has recently welcomed Igor Efimov, the Dean of the Biomedical Engineering Department at George Washington University (Washington, USA)

Efimov, a native of Krasnoyarsk, works mainly in America and France nowadays. He has created the laboratory for the study of cardiac electrophysiology, which he is now leading. Mr. Efimov is an honorary member of several scientific societies in Russia and the United States, as well as the president of the Russian-speaking Academic Science Association. We had a conversation with Igor Rudolfovich immediately after he read the lecture to the students and researchers of UrFU. 

- Igor Rudolfovich, there are well-known “dos and don’ts” when it comes to keeping the cardiovascular system healthy: have an active lifestyle, quit smoking and drinking alcohol, avoid stress, live in a comfortable climate. Does modern science have anything new to add to this, if I may say so, banal information? 

- You’re right: there’s nothing better than a healthy lifestyle, healthy diet and other well-known factors you’ve mentioned. It’s still relevant. But there are a number of advancements in cardiology which have greatly influenced life expectancy. 

The first one is the blood pressure. Even if you eat right and exercise, a genetic predisposition can cause your blood pressure to increase as you get older, and there’s nothing you can do about it. Fortunately, there are a lot of medicaments and pills that are not so expensive. If you take them carefully every day, you can keep the blood pressure normal, 120 over 80, throughout your entire life. And it is guaranteed to prolong your life by 10-20 years. The problem is compliance: people don’t take these pills. 

The second big advancement is the treatment of coronary diseases, arrhythmias. For example, coronary, vascular problems can be solved with balloon angioplasty (an expanding balloon is inserted into the vessel through a small local incision - auth.). Arrhythmia is treated with implantable pacemakers and defibrillators. These technologies have prolonged millions of lives, and life expectancy has greatly increased. 

There are a lot of achievements, but those old truths are still the most important. You can’t do better than take up running and limit fatty food, pastries and sweets. As for alcohol, most studies show that moderation is key: for example, 1-2 glasses of wine are good for the heart, but too much of it can cause problems. 

- People dream about technologies that would prevent or effectively treat diseases of the cardiovascular system. But even if such technologies are discovered, will they be available to a wide range of people? 

- Unfortunately, we are very susceptible to different trends and we believe that the achievements made "in vitro" can be immediately applied to people. For example, a huge stem cell scandal just broke out in the USA (this topic was trendy - and remains so - in Russia). But it turned out that they didn’t work in our cardiovascular area. So these technologies were abandoned, despite the fact that we spent 20 years and billions of dollars on them, and success seemed so very close. Another method has appeared recently - genetic editing, CRISPR. It works in certain simple systems, single cells. But personally, I am skeptical of this method and I don’t think that it will bring significant results in the near future. So it is difficult to predict, even if there are successful experiments on animals - worms, insects, mice, dogs, pigs. 

Animal models have taught us a lot. We’ve understood a lot of mechanisms and proposed theories of new diagnostic tools and therapies. But almost none of this is applied to clinical practice - diagnosis and therapy. For example, when the mechanism of a certain disease, which caused deaths of tens or hundreds of thousands of people worldwide became clear, many scientists rushed to make transgenic mice in order to reproduce and study this disease. Mice got the same mutations as humans, but none of the tested models of mutation correction work when applied to humans. 

An article has recently been published on this subject. A lot of work was carried out in 17 international mouse genetic engineering centers, and it showed that the probability of correcting just one genetic error is 1%, while 99% of cases fail. But the saddest thing is that while you are working on one error with a 1% chance of correcting it, there is a 99% probability that you will create other mutations somewhere in the genome and you won’t even suspect it. That is, you can neither predict these errors, nor easily detect them later. 

And since the risk is so big even for mice, I strongly doubt that the foreseeable future will see us correct something in people without negative consequences, especially in the cardiovascular system. It's a long process, because you can't jump ahead of science. Otherwise, we can face completely unjustified patient deaths and even greater mortality. 

We are more likely to witness breakthroughs in other areas, for example, in oncology. It turned out that immunotherapy is useful in the treatment of cancer. Scientists have suggested using it for the last 20-30 years, and everyone laughed at them, saying that this is utter nonsense: what connection is there between immunology and oncology? It was believed that there’s no connection, but it turned out that there is one - and very serious, too! - and it really works. For example, the former US President Jimmy Carter, who is 94 years old, defeated melanoma a few years ago thanks to immunotherapy. He had a malignant tumor that had metastasized to the brain and liver, and now he has no cancer. James Allison and Tasuku Honjo have recently received the Nobel Prize for research in this area. 

However, such new technologies (immunotherapy in particular) cost hundreds of thousands of dollars per patient. It’s clear that not many people can afford it, even in the West, in America, where insurance medicine is very developed. But I think that in 2-3 years, or 5 years, the price per patient will decrease from 300 thousand dollars to several thousand dollars, then to hundreds. The progress doesn’t stop, and methods that are expensive today will become more accessible over time. 

- During a lecture at the Ural Federal University you demonstrated a wrist gadget that can quickly record a high-resolution cardiogram. But you noted that the problem of data processing and interpretation will arise when such gadgets gather cardiograms of billions of people. Will this problem lead science to a dead end? 

- Today, many different digital technologies become more and more accessible. You can get a very detailed model of the electrophysiology of an individual patient. You can get a detailed analysis of the genetic basis of cardiovascular diseases, thousands and millions of genes that change expression in diseases. Medical centers, genomics centers generate a huge amount of data. The problem, indeed, is that biologists are unable to process this amount of accumulated, but scattered, unsystematic information (not only about the heart, but also about other organs), because they don’t have the tools of bioinformatics, mathematical analysis, big data technologies. And there are still no mathematicians who could “digest” so much information and create a coherent picture from these innumerable data sets. 

However, this is not a dead end, but a great opportunity, a task to be solved by the next generation of mathematicians who will come to biology – including specialists from Ural Federal University. I will give an inspiring example: one of my friends, a cardiologist, founded a company that came close to solving this problem, and two years later he sold it for 300 million dollars. 

- During your lecture at UrFU, you brought impressive statistics: life expectancy in the USA has increased by 10 years in just half a century, since 1958. This is just one generation. It’s mainly due to the decrease in mortality from heart disease. How did the Americans achieve such impressive results? 

- Indeed, in 1958 the death rate from cardiovascular diseases was 56 people per 10 thousand people a year, and in 2010 it was 18 people per 10 thousand people - almost 70% less. The death rate from stroke had a 80% drop, from 18 to 4 deaths.

In 2010, an article by very famous cardiologists Eugene Braunwald and Elizabeth Nabel (the dean of medical school at Harvard University) was published in the main journal about medicine - "The New England Journal of Medicine". In this article, they described the major breakthroughs in cardiology over the past 200 years, which have led to a decrease in mortality. These are the technologies I have already mentioned: stimulants, defibrillators, as well as beta-blockers that reduce blood pressure, statins - medicines for cholesterol. 

Great results can be achieved with the help of purely administrative decisions. Here is an example of such a decision, which immediately reduced the death rate from heart attack from 20% to 7%: in the US, persons with chest pain (which is a symptom of myocardial infarction) used to be put in the most distant ward, and they quietly died there without constant observation. Now, such patients are put in the nearest ward, they are given an IV drip, an electrocardiograph monitor and a defibrillator. In addition to this, of course, training is very important – the doctors have to understand biology and chemistry. 

Nowadays, the treatment of life-threatening diseases, such as myocardial infarction and stroke, combines organizational improvements, high-quality education, careful observation, the use of the latest scientific achievements and advanced technologies. This approach is the worldwide standard. I am not familiar with the Russian practice, but I suspect that there is room for improvement here, because somehow it all comes down to financing, to economic issues. Some types of therapy are quite expensive and are not used in Russia with the same frequency as in the West. For example, the number of ablations (type of surgery for the treatment of arrhythmias – auth.) per capita is significantly smaller in Russia. 

There is another example of an organizational solution with far-reaching consequences. In the US, if a person agrees to be a donor, this is indicated on their driving license. In the event of their sudden death, the permission of relatives to use donor organs is not required. There are special organizations that provide tissues and organs of the donor for transplantation - kidneys, liver, lungs, heart, and so on. Thus, on average, one donor saves eight lives. Heart preservation and transplantation is quite difficult. If the donor is older than 55, transplantation is not performed, and the heart goes to us, the scientists. In St. Louis, where I used to work, we’ve received and examined 362 living human hearts in 7 years, 45% of them are the hearts of donors, and 55% are the hearts of patients with new, donor hearts. We had the opportunity to compare diseased and healthy hearts. At the end of 2015, we started a similar program in Washington. The results of our scientific research form the basis of clinical methods and technologies. 

- What other countries besides the USA can be called leaders in the field of scientific research of the heart and blood vessels, and the treatment of relevant diseases? 

- Western Europe. In France, mortality is lower than in the US. This may be due to lifestyle and diet. Americans living in certain parts of the country, in Texas and to the north of it, prefer to drive and eat burgers, fries. Little physical activity, a lot of fatty foods - mortality from cardiovascular diseases is 3-5 times higher there than in Arizona or Florida. And the French are much more active, they have a different diet, they are slimmer. 

But it's not only that. France has a great cardiological science. In addition to Washington, I work at the University of Bordeaux. My boss, Professor Michel Haïssaguerre, a cardiologist and an electrophysiologist, invented treatments for atrial fibrillation and other arrhythmias that help more than a million patients a year around the world. This is a huge innovative contribution to cardiology. 

There are many cardiology innovators in England, Germany, Spain, Japan, New Zealand, and Australia. And, of course, in the USA. American cardiology is the leading one in the world. This is due to the fact that, among other things, huge amount of federal money is being allocated to science. The budget of the National Heart, Lung, and Blood Institute, which funds US cardiology, is estimated at $ 3 billion a year. 

- You are the head of the Russian-speaking Academic Science Association. What does it do? 

- The association RASA was established 10 years ago, in 2008, as a club of Russian-speaking scientists, to communicate with each other, to help each other. We studied in the same Russian universities, we have a lot in common. Sometimes, some of the members needed to find, for example, a Russian language teacher for their kids, and we helped them together. Over time, we started holding annual conferences at a very high level. We have the prize named after our brilliant scientist Georgy Gamow (an outstanding Soviet physicist who moved to the USA in the 1930s – auth.), who, by the way, spent 22 years working in the same George Washington university I work in now. 

Some members of our association work very actively with laboratories and universities in Russia. They have their own laboratories here; they receive grants, participate in Russian scientific conferences and even organize them. For example, I have a laboratory at the Moscow Institute of Physics and Technology, many of my acquaintances have labs at Moscow State University, in St. Petersburg, Nizhny Novgorod, Tomsk. My colleague Oleg Gusev, who works 70% of the time in Japan, has his own laboratory in his native Kazan University. Moreover, we advise many Russian government officials and regional organizations on the development of education and science. 

- If so, you probably have an idea which areas of science in our country are strong today. 

- Alas, Russia has largely lost the competencies that the Soviet Union had in different areas. As I said, due to lack of funding in the 1990s, there was simply nothing to work with, and many scientists either retired or left the country. And the youth was not interested in science. I remember that there was a joke that the most attractive professions for young people were a banker and a killer. Profession of the scientist wasn’t included in this list. 

Back in the early 2000s, I didn’t see the way out of this situation. Today, Russia retains very strong positions in mathematics, materials science, physics, chemistry, information technologies. It’s not very much compared to the USSR. But today it’s not necessary to try to embrace all (or almost all) areas of science, as was done in the Soviet Union. Even the US doesn’t do that, and small countries find unique niches for themselves and occupy them. In this regard, I liked the Skoltech structure: they understand that they will not be able to cover everything. They chose five competencies in which Russia retained its potential - space, information technology, biology, life sciences, physics - and develop them strategically. 

What else gives us hope? I’ve been traveling to Russia for 20 years, and now I finally see an active generation of students and young scientists from 20 to 30 years old. They are completely different - very confident, very active. They know languages, travel around the world, participate in international conferences. Today I recognized the faces of several young people whom I met abroad. They’re here, in UrFU, and in MIPT, and in St. Petersburg, Kazan, Siberian Federal Universities. And they ask such great questions! I haven’t been asked such professional questions even in the leading universities of the world. 

This generation will raise the Russian science, if you create decent conditions for them. PhD students need to be paid at least 70 thousand rubles, not 7. And when they become research assistants, they need to be paid five times more than the current 30 thousand rubles salary. As long as there are problems with this, the science cannot be revived in a different way. 

- Is the financial factor one of the most important ones for scientists? 

- I’m not talking just about salaries (although this is important, too), but about the scale of investment in science. Take, for example, biomedical research – they are very expensive. One good article in this area costs about 200-300 thousand dollars on average. My former students, who became young professors, received several grants in the amount of $2 million. There is no such financing in Russia yet. No one can offer Russian scientists such money at this stage of their career, and this is a big problem. Because if you do not have such money, no matter how clever and inventive you are, you will simply find yourself on the outskirts of the world science and become uncompetitive. 

It is very rare to get out there without good funding, it’s usually those who don’t need large investments - mathematicians, theoretical chemists. I know such people.

- What positions does Russia occupy in the field of research of the cardiovascular system? 

- There is a good federal program in clinical cardiology, there are cardiology centers in many leading Russian cities which meet the world-level standards, are equipped with the latest technologies, and employ qualified doctors. There are separate centers of fundamental research - in Moscow, St. Petersburg, Ekaterinburg.

For example, your group of professors led by Vladimir Markhasin (now, unfortunately, deceased) and Olga Solovieva from the Institute of Immunology and Physiology of the Ural Branch of RAS. This group has been studying electromechanical coupling in the cardiac muscle for many years; they are known worldwide for the development of very fine physiological models - not mathematical models, but models created directly on living tissue. They have very talented students, for example, Vyacheslav Guriev, who created a new-generation electromechanical model of the heart and is now working at IBM. During my visit to Ekaterinburg, Olga Eduardovna and I discussed specific projects and opportunities for collaboration. In addition, there are wonderful mathematicians at the Ural Federal University, who create excellent mathematical models. 

But in general, there is not enough fundamental cardiological science in Russia. There are very few laboratories that conduct research at the world level, few publications in leading scientific journals. The problem is partly due to the “brain drain”. I’d worked at the Institute of Biophysics Academy of Sciences of USSR in Pushchino until the 1990s, but in 1992 I was forced to leave because the funding of our institute had almost stopped. There was no money to do any experiments, and my salary was $6 per month. There was no choice. 

Another example is the Moscow Research Center for Cardiology, created by our famous cardiologist Yevgeny Chazov. At the time, this center was leading in all areas of cardiology, and hundreds of scientists - biochemists, physiologists, and so on – worked there. The Soviet Union had the strongest fundamental cardiological science, which is now virtually absent, because hundreds of scientists eventually left. I remember how they held their meetings in America: 200-300 people, and all of them became accomplished professors of leading American universities. Now, there are no centers in Russia of such research scale as the Chazov Center once was. 

So I would advise you to recreate the national fundamental cardiology, on the basis of which new generations of “advanced” clinicians will be brought up. After all, mortality from cardiovascular diseases in Russia is many times higher than in the USA. And this is a much bigger problem than oncology and other diseases. And until the fundamental cardiological science receives adequate funding and development, mortality in Russia will remain high. 

- Judging by your words, Russian cardiologists occupy a decent position in the world science. This is also evidenced by your personal example. And in your lecture at UrFU you mentioned your colleagues: Oleg Gusev, who works in Japan, Alexey Glukhov and Vadim Fedorov, who work with you in America.

- Before coming to my laboratory, Fedorov and Glukhov worked in the center of Yevgeny Ivanovich Chazov, in the wonderful laboratory of academician Leonid Rozenshtrauch, the star of the world cardiology. Now they are both very successful professors of American universities, have huge funding from the US federal sources. They would never have such funding in Russia. The choice is very simple, or rather there is no choice at all, when you want to work at the world level and receive grants worth several million dollars to conduct the most complex research. There are no such grants for young scientists in Russia. 

- By the way, there is a widespread opinion in Russia that America and Europe are engulfed by Russophobia. 

- Of course not. There can be everyday... not collisions, but tensions, misunderstandings, stupid jokes. But very rarely. In general, Americans are very polite, they can think anything, but they’ll never say something contrary to the usual notions of politeness out loud. 

- And yet, does the political aggravation between our countries affect your work abroad? 

- In the USA and France, everyone knows that I’m Russian, but nothing has changed in the grant funding or in the number of my publications. Political frictions create problems with visas. Almost none of my Russian colleagues attended this year RASA conference: they could not get a US visa. This is a real problem, and it needs to be addressed.