Heavy lines indicate normal aortic pressure (P1) and phasic coronary flow (Q1). Dashed and dotted lines indicate predicted flows when the anterior descending coronary artery is perfused with pulse pressure out of phase with myocardial systole. P2 represents proposed delayed coronary pressure; Q2R, calculated flow in presumed rigid coronary system; Q2E, calculated flow in presumed elastic coronary system 2.
Adrian’s brother, Arthur, a professor of physics at the Cornell University Graduate School of Aeronautical Engineering, lent his expertise in fluid dynamics, brought analytic support for the experimental data, and acted as a critical sounding board for the project. Most important was the environment: in the Wiggers Laboratory, where Kantrowitz was surrounded by some of the best investigators in cardiovascular physiology. To implement the concept of diastolic augmentation—later popularized by Dwight Harken as “counterpulsation” 3, 4—Kantrowitz first explored a biological approach. Intrigued by the idea of powering the system with “the eggs eaten for breakfast” 5, he wrapped a leaf of the diaphragm around the descending aorta and stimulated the phrenic nerve during diastole 6.
Upon his full-time appointment at Maimonides, Kantrowitz had applied for and was awarded three successive NIH grants ranging from $9000 to $15 000 a year for “Augmentation of Coronary Flow” and “Experimental Construction of an Auxiliary Ventricle.” During 1958–1960, Kantrowitz visited the NHI to discuss prospects for future funding. Dr. Robert Ringler, Deputy Director of the NHI, met with Kantrowitz, listened to his vision of “leaving the natural heart in place and fashioning an assist pump from autologous muscle.” Ringler was convinced. He said, “Adrian, you need a program-project grant (PPG), but that’s too big a leap from a $15 000 grant. Apply first for a multiproject grant for $200 000 to $300 000. If you manage that successfully, you’ll be taken seriously for leadership of a program-project.”
Following Dr. Ringler’s advice, in 1962, Kantrowitz obtained a 3-year, multiproject grant, “Integrated Electronic Control of Physiologic Systems,” proposing therapeutic applications using prolonged neurostimulation. In acute animal experiments, he was able to demonstrate the feasibility of stimulating the phrenic nerve to contract the aorta during diastole 6. The neuromuscular stimulation experiments led to a cluster of feasibility studies for treatment of conditions such as neurogenic bladder and paralytic ileus 7, 8. Among these was the first demonstration of a paraplegic standing and sitting under computer control 9. However, the prerequisite long-term stimulation of the phrenic nerve resulted in scar formation, a formidable challenge. Kantrowitz shifted to a mechanical device 10, 11. Work on muscle-powered cardiac assistance was picked up later as cardiomyoplasty by Stevenson, Macoviak, and others 12.
In 1965, Ringler invited Kantrowitz to submit a PPG application. The PPG would be called “Studies in Assisted Circulation.” Later that same year, at its August meeting, the Maimonides Research Committee discussed the need for a General Clinical Research Center (CRC) funded by NIH. Kantrowitz’s proposed program project was for a Categorical CRC studying mechanical methods of assisting the failing heart. It included a patient study unit. The Maimonides Research Committee Chair, distinguished hematologist Dr. Stanley Lee, was convinced (or had been so advised) that the NIH was not likely to fund two clinical research centers in a community hospital such as Maimonides. Hence, if funded, the Kantrowitz Categorical PPG, with its dedicated cardiac assist patient study unit, would foreclose an NIH-funded General CRC unit at Maimonides.
During the August 1965 Research Committee Meeting, Kantrowitz argued strongly that his program project grant would be easier to obtain than one for a General Clinical Research Center, partly because it had been invited by the NHI and partly because of the well-defined focus at the NHI on new methods of treating heart failure. He told the Research Committee that he and his staff were making an intense effort on a proposal to organize a vertical, assisted circulation research program: from concept, bench, and animal testing, through human trial. Kantrowitz had already mobilized the Chairs of each relevant specialty, including hematology at Maimonides. Each Chair participated in writing the application. Each led subprojects to answer questions on the physiological and psychological impact of prolonged mechanical circulatory assistance. Nephrologists would study renal function; hematologists, hemostatic mechanisms; psychiatrists, the reaction of recipients to living with a life-sustaining mechanical implant; and so on.
Importantly, the application also requested funds for a dedicated two-bed cardiac assist device patient study unit. It would be equipped with an advanced, custom-designed monitoring and recording system, initially, for intensive study of one patient at a time. It was, in fact, a translational medicine program project application.
Kantrowitz asked the Maimonides Research Committee to consider submitting the General and Categorical Clinical Research Center applications sequentially. A majority of the Committee concurred. The Research Committee approved Kantrowitz’s PPG application for submission to NIH by Maimonides Hospital in September 1966.
Soon after the PPG application was submitted to NIH, Research Committee Chair, Dr. Lee, sent Kantrowitz a draft CRC grant application prepared for submission to the NIH. This draft CRC application included, verbatim, the mechanical circulatory assist research plan proposed for Maimonides in Kantrowitz’s PPG application, already pending at NIH. Kantrowitz replied to Dr. Lee saying that the inclusion would be acceptable (as would be expected at NIH) “if the assisted circulation section was clearly identified as part of the pending categorical PPG application ‘Studies in Assisted Circulation’.” Dr. Lee refused, and then asked Kantrowitz to withdraw the PPG application in favor of the CRC application. Kantrowitz refused.
As far as is known, the CRC application was not submitted. The PPG was funded for 5 years, 1967–1972, in the amount of $3 million. The envisioned Categorical 2-bed Study Research Center was built during 1968, and opened in January 1969 (Fig. 2). Dr. Theodore Cooper, Director of the NHI, welcomed guests at the opening.
The Heart Surgery Study Unit at Maimonides Medical Center, funded by an NIH program-project grant, opened in January 1969. Dr. Dov Jaron, bioengineer and Director of the Assisted Circulation Research Laboratory, is seated at the custom-designed Gulton Instruments monitoring and recording system. The Unit’s Research Nurse, Cleta Lane, is at the bedside.
A “Destination” LVAD Cross-Fertilized to a Temporary LVAD: The IABP
With Kantrowitz’s earlier multiproject grant, the Assisted Circulation Research team at Maimonides had designed and fabricated an avalvular, U-shaped auxiliary ventricle implanted by means of short grafts attached to the divided ascending aorta (Figs. 3 and 4) 13. Prolonged experiments in animals with induced heart failure yielded promising results 14. To prepare for human use, which involved scaling up the canine sized blood pump and designing and building a more robust drive unit, Kantrowitz again enlisted his brother, Arthur. Arthur Kantrowitz, by then director of the AVCO-Everett Aerospace Research Laboratory in Massachusetts, brought the AVCO-Everett team of outstanding engineers into the effort. This fraternal collaboration culminated in an interruptible, left ventricular assist device (LVAD or VAD) (Figs. 5–7). It was counterpulsating, based on the concept demonstrated more than a decade earlier in the Wiggers Laboratory.
Drawing of counterpulsation concept for devices used in preclinical experiments at the Maimonides Surgical Research Laboratory. During diastole of auxiliary ventricle (AV), the bulb fills with blood as air is removed by suction, lowering resistance of the left ventricle to emptying and thus reducing its work. During AV systole, air contracts the bulb that expels its blood into the arterial tree, increasing diastolic pressure as well as peripheral and coronary flow 13.
Two views of an early prototype of the silastic auxiliary ventricle showing the angle of inset arms and relative length of woven Dacron cuffs 13.
Adrian Kantrowitz and his brother, physicist, Arthur Kantrowitz collaborated on the U-shaped auxiliary ventricle.
Courtesy of Ralph Morse / LIFE Picture Collection / Getty Images.
Dr. Tetsuzu Akutsu, Director of Experimental Surgery, and Dr. Adrian Kantrowitz discussing a preclinical experiment with the U-shaped auxiliary ventricle.
Courtesy of Ralph Morse / LIFE Picture Collection / Getty Images.
In May 1966 at Maimonides, a scaled-up U-shaped mechanical auxiliary ventricle made by the AVCO-Everett Laboratory was implanted in a 63-year-old woman, Case L(VAD)-1, in terminal heart failure. The auxiliary ventricle was intended for long-term, ambulatory treatment (“destination therapy”) of chronic heart failure. The patient could be ambulatory, detached from a drive unit, because of the blood pump’s nonobligatory function. It could be turned on and off, and on again, safely.
Case L-1 responded well to the pump hemodynamically. She was taken out of heart failure when the pump was activated. Her heart failure returned when the pump was deactivated. However, during surgery, it had been necessary to lengthen the blood pump grafts for attachment to the aorta. On postoperative day 12, Case L-1 suffered a stroke due to thromboemboli emanating from the lengthened grafts, and died the following day 15. She was the first patient to be implanted with an assist device intended to remain in the body after discharge from the hospital, when the patient returned home.
While the first Kantrowitz LVAD was being developed, the NIH, in 1964, created an Advisory Group to focus on initiatives for treatment of the failing heart. The Advisory Council of NIH recommended that NIH prioritize the development of an artificial heart. The NHI commissioned six studies on the Feasibility of a Total Artificial Heart. In 1966, Arthur Kantrowitz’s AVCO-Everett group prepared one of these reports. Under a subcontract, Adrian’s Maimonides team wrote the biomedical section. The Feasibility Studies called attention to the need for a “family of temporary emergency devices, long-term partial heart replacement devices, and total artificial hearts” for the progressive stages of heart failure 16.
In preparing their report, both Adrian and Arthur Kantrowitz were freshly impressed by the huge unmet need for temporary assistance to the acutely failing left ventricle. Each also recognized how their recent joint work on the U-shaped auxiliary ventricle for chronic left ventricular (LV) failure demonstrated the potential of counterpulsation for treatment of acute LV failure. They were both aware of the work published by Moulopoulos and Clauss (of the Kolff and Harken groups, respectively) on an IABP. These two groups had published on animal and cadaver studies but not studies in human subjects 17, 18.
Because tensions between Adrian and Arthur Kantrowitz had grown during their work together, the brothers decided to pursue the IABP separately. Adrian had the PPG funding and the multidisciplinary team in place in his Maimonides surgical research laboratory. Arthur joined with cardiac surgeons, Dr. Gerald Austen and Dr. Mortimer Buckley, at Massachusetts General Hospital 19. Paul Freed and Dr. Wladimir Schilt, a Surgical Research Associate in the Maimonides Surgical Research Laboratory, cross-fertilized their work on the U-shaped auxiliary ventricle to design and preclinically test the IABP in animals within 12 months 20. For human use, the device required only the Hospital’s Research Committee’s approval. That approval was obtained in early June 1967. Within weeks, the investigational device was used in Case 1.
At 5 o’clock the morning of Tuesday, June 29, 1967, a 45-year-old woman (Case 1) was brought to the Emergency Room at Maimonides Medical Center (MMC) of Brooklyn. Dr. Menachem Shapiro, the Internal Medicine Chief Resident, examined her. She had chest pain, was agitated, dyspneic, cyanotic, diaphoretic, pale, cold, and clammy. An ECG suggested an acute myocardial infarction. She did not respond to the maximal available medical treatment of the day: Levophed, ethacrynic acid, Solu-Medrol, and Isuprel. Her blood pressure did not rise above 60/30. Her central venous pressure rose to 14. Her medical chart notes: “cardiovascular collapse, her condition grave.”
Aware that the Hospital’s Medical Research Committee had recently approved Kantrowitz’s protocol for human trial of a new cardiac assist device to treat patients in cardiogenic shock, Dr. Shapiro called Dr. Steven Phillips. Dr. Phillips, then in his last month of surgical internship, quickly recognized that this patient might indeed be an appropriate candidate for the phase shift balloon pump (Fig. 8). At 6 am, she was admitted to the hospital. At 8:50 am, she was examined by Dr. Walter Feder, Chief of Cardiology. She was anuric. Her blood pressure was 70/30 on Levophed. At 9:20 am, she was described as “shocky.” Dr. Kantrowitz and Dr. Jordan Haller, Director of Thoracic Surgery, had joined Dr. Phillips and Dr. Feder at bedside. At 10:30 am, the team agreed that this patient met the protocol criteria. Paul Freed, a young bioengineer who co-designed the phase-shift balloon pump system, operated the drive unit. Dr. Kantrowitz asked Dr. Phillips to insert the balloon pump. Dr. Phillips inserted the balloon pump (Fig. 9) through the patient’s femoral artery, clamping it below the balloon pump insertion site, as was then specified in the protocol. At 11:32 am, cardiac assistance was begun. All vasopressors were stopped and 75 mg i.v. heparin was started. By 11:45 am, Case 1 was improving: urine output resumed; her color was better; she was no longer cold and clammy. By 12:15 pm, she was alert and drank 6 ounces of water. She was no longer in shock. At 1:00 pm, the balloon pump was turned off; labs were drawn. The patient became “very agitated,” and balloon pumping was resumed. By 1:15 pm, her condition was improved. At 2 pm, the balloon pump was turned off. Again, she became agitated. By 2:30 pm, her blood pressure was falling, and the balloon pump was restarted. The patient’s systolic and diastolic pressures gradually increased. Her urinary output increased from zero to an average of 40 cc/h. Her skin became warm and dry. The balloon pump was turned off at 6:24 pm. At 8:00 am, the balloon pump was withdrawn. It had been activated intermittently nine times, throughout 7 hours 21.
U.S. Patent 3 585 983. Inventors: Adrian Kantrowitz; Wladimir Schilt; Paul S. Freed, all of c/o Maimonides Medical Center 4802 Tenth St., Brooklyn, N.Y. 11219. Filed Mar. 5, 1968, Patented June 22, 1971.
Intraaortic balloon pump made for the Cooperative Clinical trial. The pressure sensor is at the tip of the balloon. Two EKG electrodes, one at each end of the balloon, are incorporated.
This first patient remained in the hospital for observation and was discharged 3 months later on September 17, 1967. In the following months, she was seen as an outpatient. She was in good health, except for a significant limp, related to clamping of the femoral artery during balloon pump activation. In January 1969, she was killed in an auto accident, some 18 months after she recovered from cardiogenic shock with assistance from the IABP.
Dr. Kantrowitz Is Not a Branch Store of the NIH …
By 1968, 1 year after the first IABP patient was successfully treated for cardiogenic shock, the Kantrowitz team had treated 16 patients using the balloon pump 22. The team published encouraging results, exciting global interest in the cardiovascular community (Figs. 10, 11). Cardiologists and cardiac surgeons from more than 40 countries visited the Maimonides laboratory (Figs. 12 and 13). Industry executives from device companies including Baxter, Datascope, Bard, and Ethicon came to observe animal experiments. Many visitors came repeatedly. Eager to use the balloon pump, they asked how to obtain the equipment. The Kantrowitz group had designed and fabricated the balloon pump catheters in the surgical research laboratory at Maimonides. At first, Paul Freed modified a dual-beam Tektronix oscilloscope to use as a drive unit. Later, IABP drive units were designed with the bioengineering group at Rutgers University led by Professors Walter Welkowitz and Donald A. Molony (Fig. 14) 23. No balloon pump systems were commercially available. Kantrowitz was convinced that the balloon pump’s effects needed validation by others. He wrote to Dr. Ringler asking permission to supply IABP systems to a few investigators whose institutions would reimburse funded PPG. Ringler responded stonily, “Adrian, you were peer reviewed. Your investigators were not.” Mincing no words, Dr. Ringler was informing Dr. Kantrowitz that he was not a branch store of the NIH.