Czech Marathon in the Research of Heart Assist Systems and Total Artificial Heart

This project was initiated by close cooperation between the Department of Cardiac Surgery and the Institute of Pathophysiology, Faculty of Medicine, Purkinje University (Masaryk University at present) in Brno. With great support of the outstanding founder of cardiac surgery in the former Czechoslovak Republic Professor Jan Navrátil, we decided to establish the “State Research Center for the Artificial Heart,” which was a part of the Institute of Pathophysiology. Very important support to the founding of this research center was given by the then prime minister, Mr. Jozef Lenárt.

It was accentuated that fast progress in this research can be achieved by close cooperation of cardiac surgeons, pathophysiologists, and bioengineers. My personal visit to the US research centers and direct communication with Prof. Michael E. DeBakey 1, Dr. Adrian Kantrowitz 2, 3, and Prof. Willem J. Kolff 4 in 1967 ensured important gains of basic information in this research area. After that, the multi-professional group—Research Center for the Artificial Heart—was formed, where clinical surgeons (represented by Prof. Jan Černý), pathophysiologists, pathologists, hematologists, pharmacologists, bioengineers, and mechanical and electronic engineers were concentrated. The whole group counted about 90 members, including technical staff.

Due to the “iron curtain” embargos for different technical devices, the first task of this research team was to develop the technical basis, that is, cardiac assist pumps, artificial heart (AH) devices, and driving and control devices. In contrast to the Western research centers, we missed out on the potent background of industrial companies. Only the Research Center of the Healthcare Technology in Brno, and later also the state company Rubena Náchod, entered into partnerships with our research center.

Essentially two periods of the research were constituted. The first period covered the development of the mechanical assist systems, counterpulsation, and bypass; the second period was the development of the total artificial heart (TAH). In the first period, extra-thoracic, one-way counterpulsation devices of different dimensions (28, 45, and 56 mL), intra-aortic counterpulsation balloons, and two-way heart auxiliary ventricles were developed. A very effective driving and control system for counterpulsation was developed—the Chirasist-K-4. The polyurethane used for counterpulsation balloons was of Czech origin 5–7. The bypass pumps were made of poly-methyl-methacrylate, and the left heart bypass model B-60-K-3 was very efficient. The biventricular bypass pump, model B-60-K-8, represented another attempt to solve the support of both ventricles.

Construction of the combined extra-thoracic support, bypass, and counterpulsation in one pump was another of our original projects. A two-chamber pump could simultaneously fulfill the effect of both heart-assisting principles. The combined pump features a pneumatic drive, each chamber having its own one. The bypass chamber was filled with blood pumped from the left atrium within the biological heart systole. The counterpulsation chamber started filling in late diastole, and its filling continued throughout the entire systole of the biological heart. Both chambers forced blood into the aorta in early diastole. Left heart bypass markedly reduced the volume work of the heart; the counterpulsation markedly reduced the pressure work of the left ventricle because it significantly diminished both aortic and diastolic pressures. Combination of both systems in one pump was able to bring a relief in the overloaded ventricle simultaneously. The bypass permitted instantaneous diminution of the left atrial pressure and raised cardiac output, while the counterpulsation part effectively increased the blood flow through the coronary bed 7, 8.

The further step in this concept—that is, simultaneous bypass and counterpulsation—was represented by the one-chamber pump; the crucial factor was the pneumatic valve in the output tract of the pump. The regulation of the pump function in combined regimen—when both systems are working simultaneously—depends on the correctly synchronized function of the pump diaphragm with the pneumatic valve. The control and driving of these pumps was secured by the universal synchronizing driving and control unit Chirasist-M.

Simultaneously, with the development of the mechanical heart assist systems, the fundamental basis for the research project of the second research period, that is, the total artificial heart, was developed.

Balloon counterpulsation and bypass systems were clinically tested and used at the Department of Cardiosurgery in Brno and also at some clinical institutes in the former Soviet Union 9.

Whereas the cardiac assist systems were experimentally tested mainly in dogs, the total heart experiments were performed predominantly in calves and partly in goats. Evaluation of these experiments was performed from the point of surgical problems and anatomical fitting, and further from the point of constructional and technical improvement. Exact hemodynamic, hematologic, pathological, and general pathophysiological evaluation was aimed first to the removing of negative factors that appeared during experiments. Second, this part of the project was focused on the most effective improvement of the driving system and biological adaptation of the animal, aimed to its longest possible survival. For cardiac assist systems evaluation, different forms of experimental cardiac failure were introduced 7, 10. Simultaneously with the research of cardiac assist systems and AH, the pathophysiological aspects of cardiac transplantation were studied 7, 11.

During the period of TAH development, cooperation was initiated first with the group of Prof. Valery Ivanovich Shumakov in Moscow, and later also with Prof. Zbigniew Religa in Poland. Also, the working contacts with the group of Prof. Ernst Wolner in Austria were strengthened, and experimental cooperation with the group of Prof. Horst Klinkmann in Germany was developed.

A very important visit to our center was paid by Prof. Don Olsen from Salt Lake City (Utah, USA), who gave us very important information concerning the most effective implanting procedure. He demonstrated it personally by the implantation of the UTAH-TAH-device Jarvik-3 in a calf. However, the calf (named David) with the Jarvik-3 pump survived only 6.3 days because at that time, our experience with the postoperative care was insufficient. Based on cooperation with the group of Prof. Shumakov in Moscow, we implanted the Russian TAH-KEDR with 2-day survival of the experimental animal. Later, we implanted the TAH TNS-BRNO-VII at Prof. Shumakov’s research center in Moscow and also at the Institute of Experimental Surgery of Soviet Academy of Sciences (led by the Minister of Public Health Care of the former Soviet Union, Prof. Boris Vasilyevich Petrovsky). Calf “Ruslan” survived several weeks. Prof. Petrovsky also visited our research center in Brno.

Very stimulating and highly appreciated visits in the early time of our research were paid by Prof. Hans Selye and Prof. Christian Barnard (both in 1969), and Prof. Willem J. Kolff (in 1978). Two European Society for Artificial Organs satellite symposia were organized (1988 and 1990), with the participation of world leading scientists in AH research. At this occasion, commemorative medals of Brno AH research were handed over to prominent persons in AH research.

Very intensive cooperation was performed with the Institute of Medical Electronics of the Tokyo University with Prof. Kazuhiko Atsumi and Prof. Kou Imachi. This cooperation has continued even after the experimental work at the Brno Research Center was terminated, and it is lasting until now.

During the period of the TAH research, constructional development and experimental verification of 12 pneumatically driven TAH models was performed. The experiments performed with the poly-methyl-methacrylate pumps TNS-BRNO I, IV, V, and VI (in several tens of calves) did not exceed 31 days.. In all TAH pumps, the polyurethane (PUL) valves of our own construction were used, flap type in inflow and roof type in outflow tract.

The most successful experiments with the poly-methyl-methacrylate TNS-BRNO-II pumps lasted from 31 to 175 days and were performed in 23 calves. With the polyurethane pumps, one animal in experiment with the symmetrical pump TNS-BRNO-III (100/95 cc) survived 104 days. Polyurethane used in our experiments was of Czechoslovak origin. Later, we started with the asymmetrical construction of the devices. In the symmetrical device, the flap inflow valve came in contact with the diaphragm. When the diaphragm was covered with thrombi or calcified deposits, the micro-particles were liberated into circulation as micro-thromboemboli. If the driving diaphragm and the pump housing were asymmetrically lifted over the inflow tract, the contact was minimized and simultaneously the undulating movement of the driving diaphragm greatly improved the evacuation process from the blood chamber with elimination of the so-called dead corners 12, 13.

With this constructional improvement, the TNS-BRNO-VII polyurethane device (120 mL) was put into experiments; 37 calves in the experimental group survived from 39 to 314 days. In one of the experiments, with 157 days of survival, the TNS-BRNO-VIII device (120 cc) with the flap valve also in the outflow tract was inserted. The TNS-BRNO-VII TAH for clinical use (80 cc) was used in six patients with 10 days survival.

Four comparative experiments with the ROSTOCK pellethane device (120–80 cc) equipped with Björk–Shiley valves were successfully performed, with 78–226 days of survival.

The most successful experiment with the TNS-BRNO-VII was in the calf called “Juan”; it survived 314 days, which was at that time the European record. This result was very valuable, as by that time there were only six active AH centers in Europe. In all our experiments, the control and driving system of our original construction Chirasist-TN was used. In the last device, TNS-BRNO-IX (120 cc), the small additional flap valve was attached to the main outflow valve which better secured the blood streaming on the back of the main valve, thus preventing the thrombi formation at this site 14, 15.

Unfortunately, due to unexpected and sudden interruption of the financial support of our research center, caused by negative attitude of the new Czechoslovak government authorities toward this research, it was not possible to verify this last device in experimental conditions. For the same reason, also the experimental verification of the TNS-BRNO-VII TAH with the Japanese jellyfish valves developed by Prof. K. Imachi was impossible. The irrational action of the Czechoslovak government to our research after the “Velvet Revolution” in 1989 did not enable us to start the last and most important phase of research—finishing the electromechanical, totally implantable device and its experimental verification.

Except for the calves, we have also performed experiments in goats—a total of 10 experiments with survival of less than 31 days. In one goat, “Hannibal,” with the intra-thoracic implantation of the TAH-TNS-BRNO-VII (80 cc), 184 days of pumping were reached, which was the world record survival in goats with the intra-thoracic pump.

We have carefully studied hemolysis as a multifactorial state; attention was paid to the endogenous and exogenous factors, and the role of the red blood cell membrane resistance to the pumping regimen 16. Very intensive study focused also on the etiopathogenesis of the diaphragm mineralization; very good results in prevention of this state were reached by the reversed calciphylaxis procedure called “anacalciphylaxis” 17, 18.

Based on our intense study of pathogenesis of high arterial and venous pressure, especially in the later stages of pumping, we have developed pathophysiological principles to prevent it 19. The analysis by electron microscopy showed more expressed lesions in liver and kidney than in the lung 20. The study of the TAH infections enhanced the use of more specifically developed antibiotics focused exclusively to the slime biofilm protected bacteria on the diaphragm. Also, new procedures aimed to the specific stimulation of the mechanisms of immune defense in the TAH bearers were studied 21.

In all our experiments, we have consistently kept the pulsatile regimen as our microcirculatory study showed the physiological prevalence of the pulsatile pumping 22. Recently, we have confirmed in close cooperation with the Department of Biomedical Engineering, Tokyo University that this concept might be more realistic than the pulseless pumping 23, 24.

When our project was unjustifiably stopped, it was necessary to publish all accumulated data and to accomplish the information about our experiences. By our two monographs on AH research, we tried to draw near to the splendid monograph “Artificial Heart” from Tetsuzo Akutsu 25.

After we lost the experimental basis, we could share some of our experiments in the cooperation with the group of Prof. Kou Imachi in Tokyo; this collaboration is maintained until now.

I would like to finish my retrospective look by the Chinese proverb: If you want to go 10 000 miles, you must make the first step. Many miles will have to be passed before the definite, usable, and clinically reliable TAH system will become a clinical reality, and several future generations will surely participate in this fantastic project and—possibly—realize it.

I am proud of the fact that the whole constructional, mechanical, electronic, surgical, and pathophysiological development of this project was performed in one place in our research center at the Institute of Pathophysiology of the Faculty of Medicine in Brno and only by our own forces.

And I must say that I much appreciate and I am proud to be a man who received the prestigious Japanese award, the Akutsu Prize, which was personally handed to me in 1995 by one of the world pioneers of the AH research, Prof. Tetsuzo Akutsu.

Finally, I would like to thank all my coworkers who enabled us to push one important project of contemporary medicine far forward, and I thank them for the beautiful time that we have spent together.