MEDICINE / CARDIOLOGY

Excellence in the heart

Pioneering advances in treatment and research have made InCor a center of reference in Latin America

Bosom buddy: pediatric artificial ventricle developed at InCor

Imagem: Léo RamosBosom buddy: pediatric artificial ventricle developed at InCorImagem: Léo Ramos

In the basement of the Heart Institute (InCor), in Pinheiros, São Paulo State, there is a laboratory with simulators, presses and other machines—some heavy, others of high precision. It is here that some Brazilian versions of an artificial ventricle are being produced on an experimental scale. The ventricle consists of a small chamber made ​​of a synthetic polymer, divided in two by an impermeable membrane. Connected to the heart via cannulas during surgery, the artificial ventricle helps to pump blood when heart function is greatly compromised. The latest model produced at InCor is a pediatric version of the ventricle, which is able to pump 15 milliliters of blood per beat. It was designed to be implanted in children who have only a few months to live and require circulatory support while awaiting a heart transplant. Today children who need this type of device are underserved in Brazil. The imported versions are very expensive. The first was approved by the health authorities in the United States in 2011 and costs about $100,000, a price that makes using it practically impossible for the Brazilian public health system. “The scientific and technological challenges encountered in these types of projects, associated with the specifics of the market, hinder its development by the domestic industry here,” says Idágene Cestari, director of InCor’s Biomedical Technology Center, who came up with the idea of developing a pediatric ventricle in Brazil a number of years ago, when an artificial ventricle for adults was tested in Germany. “Our ventricle was specifically developed with Brazil’s Unified Health System (SUS) in mind,” she says.

The InCor pediatric ventricle has been implanted in pigs and sheep in partnership with the pediatric surgical team led by Marcelo Jatene and will be clinically evaluated after approval by the Brazilian Health Surveillance Agency (ANVISA). The pediatric version, evolved from a previous model, pumps 60 milliliters of blood per beat. It was developed by InCor and approved for experimental use in adults. A pilot batch is ready for evaluation by six Brazilian hospitals in 2015.

Construction of the main building of the USP School of Medicine in 1920

Imagem: Museum collection of the USP School of MedicineConstruction of the main building of the USP School of Medicine in 1920Imagem: Museum collection of the USP School of Medicine

Preventable deaths
InCor researchers have been pursuing the goal of building a Brazilian artificial ventricle for at least 20 years. More than 70,000 heart surgeries (such as coronary bypasses) are performed every year in Brazil, including 15,000 pacemaker implants and 300 heart transplants. These are impressive numbers, but not enough. Today 300,000 Brazilians die each year from heart disease. A great many of these deaths could be prevented with increased use of diagnostic tests and preventive measures. For patients who are lucky enough to receive an early diagnosis, the risk is in the time spent waiting in line for a heart transplant. Many die while waiting for a compatible donor and would be more likely to survive if they could get an artificial ventricle. “An artificial ventricle is indicated for patients with severe heart failure,” says Dr. Noedir Stolf, a cardiologist and former director of InCor. “The implant is meant to keep the patient alive while waiting for a donor.”

In 1993, Dr. Stolf, at InCor, performed the first implantation of an artificial ventricle in Latin America, in a procedure that has been repeated one to three times a year.  In the U.S. there are about 2,000 such procedures every year. The only reason the surgery is not more widespread is because of the high cost of imported ventricles. “The equipment itself costs $100,000, and because of taxes here, each imported unit ends up costing at least $300,000,” says Dr. Stolf. Making an artificial ventricle in Brazil would mean reducing the cost of this surgery.

“The use of this form of support is increasing; today about 40% of patients use an artificial ventricle before transplantation,” says Dr. Fábio Jatene, current director of InCor. “We decided to use our own technology to begin to develop the simplest models, to be used for just a matter of weeks.”

First class: students in 1914 and Arnaldo Vieira de Carvalho, first row, fifth person seated from the right

Imagem: Museum collection of the USP School of Medicine First class: students in 1914 and Arnaldo Vieira de Carvalho, first row, fifth person seated (from the right)Imagem: Museum collection of the USP School of Medicine

Pioneering advances
The development of artificial ventricles is part of the pioneering work of the surgeons and engineers of InCor. A pioneering ethic, incidentally, is one of the main characteristics of both the institute and the institution in which it originated, the University of São Paulo School of Medicine (FMUSP). Built in 1912, over 100 years after the founding of surgery schools in the states of Bahia and Rio de Janeiro by Dom João VI (John VI of Portugal), what was known as the São Paulo School of Medicine and Surgery went on to take the lead in medical instruction and research in Brazil.

Its founder and first director, Arnaldo Vieira de Carvalho (1867-1920), followed the model of the most advanced medical schools of the time, which combined treatment with medical research. From the beginning, the School introduced the most modern techniques, assimilated by professors and students during overseas study trips. Funding for construction of the building that would house the School (opened in 1931), the purchase of equipment, collections of books and periodicals for the library, and the first scholarships for Brazilian physicians to study in the United States came from the Rockefeller Foundation. The counterpart to this funding would be the construction, by the government of São Paulo, of a hospital to serve the people.

Between the opening of the FMUSP headquarters and that of Hospital das Clínicas (HC), in 1944, professors and students experienced their baptism by fire. Within three months of the Constitutionalist Revolution of 1932, when the people of São Paulo rebelled against the government of Getúlio Vargas, physicians and students improvised field hospitals on the frontlines against the Vargas forces coming from the states of Rio de Janeiro, Minas Gerais and Paraná. The surgeries and other treatments performed on the wounded under adverse conditions were valuable lessons learned for the purposes of organization of the School, which has always maintained a strong tradition in surgery. Among surgeons trained at the School, a key figure was Euryclides de Jesus Zerbini (1912-1993), head of the former Cardiac Clinic Center of USP’s Hospital das Clínicas, the birthplace of InCor.

The first heart surgery to use cardiopulmonary bypass in the world was performed ​​in the United States in 1953. In Brazil, Dr. Hugo Felipozzi (1923-2004) performed this procedure in 1956 at the Santa Casa de São Paulo Hospital. That same year, Dr. Zerbini and his students Adib Jatene (1929-2014) and Delmont Bittencourt (1921-1991) went to the United States to study the most advanced techniques. Upon his return, Dr. Zerbini performed ​​the first ever heart surgery at USP’s medical school and hospital. “Drs. Bittencourt and Jatene came back with the idea of setting up a workshop in the hospital’s basement to make heart valves and clamps for use in surgery,” says Dr. Stolf. One of the main projects was building a heart-lung machine.

The advances in cardiac surgery at Hospital das Clínicas made it a center for excellence in Brazil and Latin America. The increasing numbers of patients, students and visitors from other countries necessitated its move from the old Cardiac Clinical Center, which in 1963 was renamed the Institute of Cardiopulmonary Diseases. The goal of the restructuring was to increase the financial capacity and build a headquarters site, which opened in 1975.

Transplants
Meanwhile, its cardiologists continued to innovate. The next step was to perform transplants. In December 1967, South African physician Christiaan Barnard performed the first human-to-human heart transplant in history. Six months later Dr. Zerbini performed the same feat in Latin America. That same year, Dr. Adib Jatene’s team would perform the first myocardial revascularization operation, the coronary artery bypass, at the Instituto Dante Pazzanese de Cardiologia in São Paulo.

Then in 1968, a team led by Dr. Marcel Machado performed Brazil’s first liver transplant at Hospital das Clínicas. The patient survived one week. There were four more attempts before 1974. From the beginning, rejection of the implanted organ and the lack of donors were the major impediments. With the introduction of immunosuppressives abroad, the rejection rate fell in surgeries and patient survival increased. The first successful liver transplant in Brazil took place only in 1985 when the team led by Dr. Silvano Raia at FMUSP was able to prolong the patient’s life for 18 months. Three years later his team would perform the first donor transplantation: a mother donated one-third of her liver to her daughter.

After mastering transplant techniques, surgeons began to focus more on the problem of organ rejection. In 1985, Dr. Jorge Kalil Filho set up the Immunology Laboratory of FMUSP, which contributed to the body of research on the surface molecules of the endothelial cells involved in rejection.

In the case of the coronary bypass, the challenge involved increasing the durability of a saphenous vein before it had to be replaced in the patient. The vein is a specialized vessel for the transport of small volumes of blood under low pressure. Changes in conditions cause excessive thickening of the innermost layer of cells, accelerating the accumulation of fat deposits, which obstruct 10% of the bypasses in less than a decade.

A method to reduce or prevent premature clogging of these vessels has yet to be found. Dr. José Eduardo Krieger and his team at InCor’s Laboratory of Genetics and Molecular Cardiology have been studying this phenomenon since 2004. They are simulating the problem in rats whose carotid artery blood flow is partially diverted to the jugular vein. In the walls of the veins, the increased pressure activates genes that are more active in the arteries, which favor the thickening of the vessel walls. This is a sign that the vein is trying to adapt to the new conditions. The problem is that in many cases the adaptation gets out of control and causes clogging. Such conditions favor the development of atherosclerosis. The experimental rat model corresponds to what is seen in bypass patients. Dr. Krieger’s team is trying to develop gene therapies to reverse the situation.