Historical Perspective of Cardiovascular Devices and Techniques

20 Historical Perspective of Cardiovascular Devices and Techniques

DEE M. MCMANUS, BS, MONICA A. MAHRE, BS, AND PAUL A. IAtZZO, PhD

CONTENTS

INTRODUCTION CROss-CIRCULATION LILLEHEI-DEWALL BUBBLE OXYGENATOR HEART BLOCK AND THE DEVELOPMENT OF THE PACEMAKER HEART VALVES OTHER UNIVERSITY-AFFILIATEDMEDICAL DEVICES FOOD AND DRUG ADMINISTRATIONREGULATES MEDICAL DEVICES MEDICAL ALLEY CARDIOVASCULAR PHYSIOLOGY AT THE UNIVERSITY OF MINNESOTA REFERENCES

1. INTRODUCTION played an integral role in supporting both research and the clini- The era from 1950 to 1967 was an incredible time of inno- cal training of surgical residents. To that end, Wangensteen vation within the University of Minnesota's Department of instituted a 2-year research program for all residents; this sur- Surgery in the newly emerging field of open heart surgery. gical PhD program was the only one in the country at its incep- There were many reasons for this, but most importantly it was tion, and it still exists today. attributable to the following: (1) the university had excellent An important part of the innovative surge was that many facilities, including a unique privately funded 80-bed heart surgical residents were returning from World War II, which had hospital for pediatric and adult patients, and (2) the Depart- recently provided them with life-and-death situations when ment of Surgery was led by a chair, Owen H. Wangensteen, managing MASH (mobile army surgical hospital) units--they MD, who "created the milieu and the opportunities for great had little or no fear of death. Their generation was not afraid of achievements by many of his pupils," and was considered the "pushing the envelope" to help patients. By today's standards, "mentor of a thousand surgeons" (Fig. 1, Table 1) (1). they would be viewed as "mavericks" or "cowboys," but in fact More specifically, Dr. Wangensteen encouraged his medical they had little to lose, as on the battlefields where they received students to "step out of the box," look at problems in different their early exposure; their patients were dying or had little ways, and not assume that those who went before them had all chance of survival without the novel techniques successfully the answers. He also believed strongly in collaborations with implemented in Minnesota. the basic science departments, specifically the Department of One of these young war-experienced surgeons was C. Walton Physiology, with the department head, Maurice Visscher, who Lillehei, who returned to the University of Minnesota in 1950 to complete his surgical residency after leading an Army MASH From: Handbook of Cardiac Anatomy, Physiology, and Devices Edited by: P. A. Iaizzo © Humana Press Inc., Totowa, NJ unit in both North Africa and Italy (Fig. 2). Walt, as he was

273 274 PART IV: DEVICES AND THERAPIES / MCMANUS ET AL.

Table 1 Department of Surgery at the University of Minnesota: Chairs/Interim Heads Surgery department chair~interim head Position Years served Arthur C. Strachauer Department chair -1925, 1927-1929 Owen H. Wangensteen Department chair 1930-1967 John S. Najarian Department chair 1967-1993 Edward W. Humphrey Interim chair 1993-1994 Frank B. Cerra Interim chair 1994-1995 David L. Dunn Department chair 1995-Present

Fig. 1. "The Chief," Dr. Owen H. Wangensteen, the youngest Surgery Fig. 3. Clarence Dennis with the first heart-lung machine at the Uni- Department chair at age 31 years (chair from 1930 to 1967). versity of Minnesota.

called, was a bright (he completed his master's and doctoral degrees during this time also) and impulsive maverick, always pushing to the next level of care for his clinical patients, for whom he had great empathy. Lillehei and his team launched many surgical innovations during this period, primarily because of their hands-on research experiences in the experimental dog laboratories. Interestingly, prior to 1950, the heart was considered the core of human emotion, with a role in human feelings toward others and even the soul itself. It was not until the medical profession began to view the heart more physiologically, as a pump or machine within the body, that researchers and clini- cians began to develop new ways to repair and replace worn-out parts of the heart; innovations in the field of cardiac surgery then flourished (Table 2). Such innovation became prominent at the University of Minnesota. Soon thereafter, Dr. Clarence Dennis designed the first heart-lung machine for total cardiopulmonary bypass, which was subsequently tested successfully on dogs (Fig. 3). However, when Dennis and his team used the heart-lung machine in the clinical area for the first time on April 5,1951, the patient died because of complications. A second patient also died during surgery from massive air embolism. Not long after, Dr. Dennis moved his machine and most of his team to New Fig. 2. Walt Lillehei in Army uniform. York City (I). CHAPTER 20 / HISTORICAL PERSPECTIVES 275

Table 2 University of Minnesota Milestones 1887 New standards requiring medical students to pass exams and gain medical examining board approval (led by Medical School Dean Perry Millard) 1911 Minnesota became the first state to mandate hospital internships for medical students 1930s Discovery of link between cholesterol and heart disease (Ancel Keys) 1950 First adaptation of the mass spectrograph (Alfred Nier) 1951 First attempt to use a heart-lung machine (Clarence Dennis) 1952 First successful open heart surgery using hypothermia (F. John Lewis) 1953 First jejunoileal bypass (Richard L.Varco) 1954 First open heart procedure using cross-circulation (C. Walton Lillehei) 1954 First surgical correction of tetralogy of Fallot (C. Walton Lillehei) 1955 First successful use of the bubble oxygenator (Richard DeWall) 1958 First use of a small, portable, battery-powered pacemaker (Earl Bakken) 1963 First human partial ileal bypass (Henry Buckwald) 1966 First clinical pancreas transplant (William D. Kelly and Richard C. Lillehei) 1966-1968 First prosthetic heart valves (Lillehei-Nakib toroidal disk, 1966; Lillehei-Kaster pivoting disk, 1967; Kalke-Lillehei rigid bileaflet prosthesis, 1968) 1967 Bretylium, a drug developed by Marvin Bacaner, saved the life of Dwight Eisenhower 1967 World's first heart transplant (Dr. Christiaan Barnard, trained by C. Walton Lillehei) 1968 First successful bone marrow transplant (Robert A. Good) 1969 Invention of implantable drug pump (Henry Buckwald, Richard Varco, Frank Dorman, Perry L. Blackshear, Perry J. Blackshear) 1976 Medical Device Amendment to FDA Cosmetic Act 1977 First implant of St. Jude mechanical heart valve at University Hospital 1988 HDI/Pulse Wave ® profiler founded (Hypertension Diagnostics Inc. [St. Paul, MN], Jay Cohn, Stanley Finkelstein). 1993 Angel Wings transcatheter closure device invented (Gladwin Das) 1994 First successful simultaneous pancreas-kidney transplant using a living donor (David Sutherland) 1995 Amplatzer Occlusion Devices founded (AGA Medical Corp., Kurt Amplatz) 1997 First kidney-bowel transplant (Rainer Gruessner) 1999 CardioPump Device evaluated (Keith Lurie et al.) 2000 By 2000, University alumni have founded 1500 technology companies in Minnesota, contributing at least $30 billion to the state's economy 2000 By 2000. University's medical school has produced more family doctors than any other institution in the United States

The next major University of Minnesota (worldwide) milestone in cardiac surgery was the first open heart surgery using hypothermia on September 2, 1952, by Dr. F. John Lewis (Fig. 4). This procedure, suggested by Dr. W.G. Bigelow of Toronto, lowered the body temperature of patients 12-15'-' to reduce their blood flow, thereby reducing the body's need for oxygen. Brain cells would die after 3--4 min at normal temperature without oxygen, but hypothermia allowed Dr. Lewis and his university research team (Drs. Mansur Taufic, C. Walton Lillehei, and Richard Varco) to successfully complete a 5.5- min repair of the atrial septum on a 5-year-old patient. This was recognized as a landmark in the history of cardiac surgery; until this time, no surgeon had succeeded in opening the heart to perform intracardiac repair under direct vision. Hypothermia with inflow stasis proved to be excellent for some of the simpler surgical repairs, but it was inadequate for more extensive cardiac procedures. "The basic problem was the lack of any means to rewarm a cold, nonbeating heart" (2). The next milestone, although not accomplished at the Uni- versity of Minnesota, occurred on May 6, 1953, when Dr. J. Gibbon closed an atrial septal defect using a pump oxygenator Fig. 4. In this 1952 photo, Richard L. Varco (left) and F. John Lewis for an intracardiac operation. Although this first success with stand behind the hypothermia machine that they used during the the pump oxygenator was well received, it aroused surprisingly world's first successful open heart surgery. 276 PART IV: DEVICES AND THERAPIES / MCMANUS ET AL.

Fig. 5. Diagram of cross-circulation.

little excitement or enthusiasm among cardiologists and car- tion was considered unacceptable and even immoral by some diac surgeons at that time, likely because other centers had critics. The risks to the donors were: (1) blood incompatibility, launched their own experiments with bubble oxygenators. (2) infection, (3) air embolism, and (4) blood volume imbal- Interestingly, Gibbon was never able to repeat his one clinical ance. Regardless, Lillehei and his team completed 45 such success; he ultimately became discouraged and did not use the operations between 1954 and 1955. In early 1955, three addi- pump oxygenator again. tional bypass methods were introduced and successfully There was a common scenario, namely, good results employed, including: (1) perfusion from a reservoir of arterial- with acceptable survival in the experimental animals ized blood, (2) heterologous (dog) lungs as an oxygenator, and but nearly universal faihu'e when the same appara- (3) the DeWall-Lillehei disposable bubble oxygenator (2). tus and techniques were applied to human beings. The likely single most important discovery that contributed Thus, many of the most experienced investigators to the success of clinical open heart operations was the realiza- concluded with seemingly impeccable logic that the tion of the vast discrepancy between the total body flow rate problems were not with the perfusion techniques or thought necessary and what was actually necessary. Lillehei the heart lung machines. Rather, they came to believe and his team are credited with applying the findings of two that the "sick human heart" ravaged by failure, could British surgeons (A. T. Andreasen and F. Watson) who had not possibly be expected to tolerate the magnitude of identified the azygos factor--the ability of dogs to survive up the operation required and then recover with good to 40 rain without brain damage when all blood flow was stopped output, as occurred when the same machines and except through the azygos vein. techniques were applied to healthy dogs. Thus, dis- Specifically, Morley Cohen and Lillehei hypothesized that couragement and pessimism about the future of open when blood flow was low, the blood vessels dilated to receive heart surgery was widespread. (2) a larger share of the blood; the tissues absorbed a much higher proportion of the oxygen compared to normal circulation. Pre- 2. CROSS-CIRCULATION viously, it was thought that basal or resting cardiac output at Extracorporeal circulation by controlled cross-circulation 100-160 mL/kg/min was the required safe maintenance during was introduced clinically on March 26, 1954 (Fig. 5). The use cardiopulmonary bypass. In contrast, the azygos flow studies of cross-circulation for intracardiac operations was an immense showed that 8-14 mL/kg/min maintained the physiological departure from established surgical practice at the time and was integrity of the vital centers, but Lillehei added a margin of the major breakthrough that motivated innovations in the area safety and set his basic perfusion rate at 25-30 mL/kg/min. This of open heart surgery (3). The thought of taking a normal healthy approach reduced excessive complications of blood loss, exces- human being into the operating room to provide donor circula- sive hemolysis, abnormal bleeding, and renal shutdown (2). CHAPTER 20 / HISTORICAL PERSPECTIVES 277

Altogether, 45 patients (aged 5 months to 10 years) under- went open heart surgery with cross-circulation at the Variety Club Children' s Hospital (Minneapolis, MN). Prior to this surgery, these patients had lesions that were considered hope- lessly unrepairable. Of this group, 49% of the patients lived to be long-term survivors (longer than 30 years) and to lead normal productive lives; 11 of the female long-term survivors subsequently became pregnant and gave birth to a total of 25 children, all free from any congenital heart defects. In addition, all 45 donors survived, with only 1 donor experiencing a significant complication. It should be noted that, during this period of time, an intense competition/collaborative relationship existed with the Mayo Clinic (Rochester, MN), the only other site where open heart surgery was routinely being performed. Lillehei recalled in his interview with G. Wayne Miller (author of King of Hearts [Random House, New York, 2000]) that the Mayo Clinic operated 7 days a week, so on Saturdays when Lillehei's team Fig. 6. Mayo Clinic's heart-lung machine was as big as a Wurlitzer did not perform surgery, they would travel to the Mayo Clinic organ; it cost thousands of dollars and required great skill to operate. and watch Dr. John Kirklin and his colleagues (Miller, G.W., Transcriptions of audio tapes for book, University of Minne- sota Archives). Dr. Kirklin was successfully using a modification of the Gibbon heart-lung machine and, after observing his achievements, Lillehei began a slow transition away from cross-circulation and toward using a heart-lung machine, but one of his own design (Fig. 6). In the beginning, Lillehei used the heart- lung machine for simpler, more straightforward cases and continued using cross-circulation for the more complicated cases. Although its clinical use was short-lived, cross-circulation is still considered today as an important stepping stone in the development of cardiac surgery.

3. LILLEHEI-DEWALL BUBBLE OXYGENATOR John Gibbon MD, from Boston, Massachusetts, invented the cardiopulmonary bypass procedure and performed the first intracardiac repair using extracorporeal perfusion in 1953. His bubble oxygenator, which looked surprisingly like a com- puter, was manufactured and financed by IBM; this achieve- ment stimulated rapid development of the knowledge base and equipment necessary for accurate diagnoses of cardiac disease and successful intracardiac operations. It was recognized that the main problems with film oxygen- Fig. 7. University of Minnesota' s bubble oxygenator cost $15 and was ators were (1) poor efficiency, (2) excessive hemolysis, (3) large easy to use. Richard DeWall is shown here with his model in 1955. priming volumes, and (4) the development of bubbles and foam in the blood. All designs required blood flows of 2.2 L]m2/min, usually three to four units of blood for priming, and another two units of blood for the rest of the circuit. Furthermore, after each use, the machine had to be broken down, washed, rinsed in a huge technological breakthrough in 1955 by developing a hemolytic solutions, reassembled, resterilized, and reconfig- bubble oxygenator with a unique method for removing bubbles ured. from the freshly oxygenated blood (Fig. 7). In DeWall's design, During this era, Richard DeWall came to work at the Univer- blood entered the bottom of a tall cylinder along with oxygen sity of Minnesota, initially, as an animal attendant in Lillehei's passed through sintered glass to create bubbles. As the bubbles research lab. DeWall would manage the pump while the anes- and blood rose, gas exchange occurred at the surface of each thesiologists would take breaks, and soon he began to take an bubble. At the top of the cylinder, arterialized bubble-rich blood interest in the problems associated with oxygenating blood. passed over stainless steel wool coated with silicone antifoam; Eventually, Lillehei challenged DeWall to find a way to elimi- it then traveled through a long helical settling coil to allow nate bubbles in the procedure. Subsequently, DeWall produced bubbles to rise slowly and exit the blood. 278 PART IV: DEVICES AND THERAPIES / MCMANUS ET AL.

4. HEART BLOCK AND THE DEVELOPMENT OF THE PACEMAKER An unexpected clinical benefit from the development of open heart surgery was the discovery of a revolutionary new concept for treatment of complete heart block. Heart block is caused when the electrical impulse that begins high in the right atrium fails to reach the pumping chambers--the ventricles. Deprived of their normal signal, the ventricles may beat slowly on their own, but at a rate that limits activity and typically results in heart failure. In the early intracardiac procedures for more dif- ficult surgeries, it was subsequently determined that complete heart block occurred because of injury of the heart's conduction system, induced by stitches in about 10% of the operations. With the existing treatment for complete block, the application of positive chronotropic drugs or electrodes to the surface of the Fig. 8. Richard DeWall and Vince Gott look at the first commercially chest, there were no 30-day survivors. manufactured sterile bubble oxygenator in 1956. In 1952, Paul Zoll, a cardiologist in Boston, utilized the first human pacemaker unit on a patient--a large tabletop external unit with a chest electrode. It was successfully used to resusci- tate patients in the hospital, but delivered 50-150 V, which was Two important components in the Lillehei-DeWall bubble incredibly painful for children and typically left scarring and/or oxygenator were the tubing and the silicon antifoam solution. blisters. In addition, it used an alternating current electrical The tubing was Mayon polyethylene tubing (typically used in source, limiting the mobility of the patient to the length of the the dairy industry and in the production of mayonnaise), avail- cord. Spurred by such adversity, Lillehei and his research team able from Mayon Plastics (Hopkins, MN), with a company chief found, in 1956, that an electrode directly connected to the ven- executive officer who was a classmate of Lillehei's and a gradu- tricular muscle from a pulse generator producing repetitive elec- ate of the university's chemical engineering program. The sili- trical stimuli of small magnitude (5-10 mA) provided very cone antifoam solution, Antifoam A, was used to coat the tubing effective control of the heart rate and an 89% survival rate for to prevent foaming of the liquids transported. patients with prior heart block. The oxygenator was wonderfully efficient; animals (and later On January 30, 1957, a pacemaker lead made ofa multistrand, patients) did not show detectable effects of residual gas emboli. braided stainless steel wire in a Teflon sleeve was implanted More important, this design eventually led to the development into a patient's ventricle myocardium, with the other end of a plastic, prepackaged, disposable, sterile oxygenator that brought through the surgical wound and attached to external replaced the expensive stainless steel, labor-intensive screen, stimulation. The utilized pacemaker (pulse generator) was a and film devices. An economic and reliable oxygenator had Grass physiological stimulator borrowed from the university's arrived, and the medical industry began to use disposable com- Physiology Department. This procedure was designed for short- ponents for the heart-lung machine. term pacing, with removal of the wires 1-2 weeks after the Two years after its introduction, the DeWall-Lillehei bub- patient's heart had regained a consistent rhythm. ble oxygenator had been used in 350 open heart operations at Following near disaster for a pacemaker-dependent patient the University of Minnesota. DeWall steadily improved the when the electrical service failed in the University hospital device through three generations of models, but it remained a because of a storm, Lillehei asked his medical equipment very simple, disposable, and heat-sterilizable device that could repairman, Earl Bakken, to design a battery-powered, wear- be built to accommodate only the amount of blood required for able pacemaker to improve the patient's mobility (Fig. 9). This each patient and then discarded. Bakken did, using a circuit modified from a diagram for a In 1956, another one of Lillehei's residents, Vincent Gott, transistorized metronome in Popular Electronics magazine as invented a bubble oxygenator in which DeWall's helix design a model (Fig. 10); a few months later, such as device was used was flattened and enclosed between two heat-sealed plastic clinically on April 14, 1958. sheets (Fig. 8). This sheet bubble oxygenator proved to be the Bakken's transistor pulse generator made a miraculous key to subsequent widespread acceptance of the device for "overnight" transition from bench testing to clinical use; this open heart surgery because it could be easily manufactured and invention then set the stage for creation of the cardiac pacing distributed in a sterile package; it was inexpensive enough to be industry. For the next decade or so, it would become common disposable. The University of Minnesota licensed rights to practice to put new devices or prototypes (even fully implant- manufacture and sold the device to Travenol Inc. (Minneapolis, able ones) into clinical use immediately and then iron out the MN). With the bubble oxygenator and techniques developed by imperfections based on the accumulation of clinical experi- Lillehei and his colleagues, the University of Minnesota had ences. This humanitarian practice developed because most of become prominent for the making open heart surgery possible the early patients were close to death, and no other treatments and relatively safe (4). existed (5). Eventually, Medtronic, Inc. (Minneapolis, MN), CHAPTER 20 / HISTORICAL PERSPECTIVES 279

Fig. 9. C. Walton Lillehei and young patient with battery-powered, wearable pacemaker. I

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under B akken's leadership, became the world's leading manu- use. Nevertheless, the 5800 pacemaker became the symbol for facturer of cardiac pacemakers, beginning with the Model Medtronic's shared belief in medical progress through technol- 5800. ogy; this was celebrated during an unveiling, at his retirement The first generation of the 5800 pacemaker was black, but celebration in 1994, of a bronze statue of Earl Bakken holding was quickly changed to white to look cleaner and more sanitary the 5800 pacemaker. Years later, the 5800 was viewed by (Fig. 11). Between 1959 and 1964, only a few hundred pace- Lillehei as a technological watershed: "It was the fruit of inter- makers were sold because of the reusability of this system and disciplinary collaboration, exemplifying the marriage of medi- the short-term postsurgery focus; orders soared once the pace- cine and technology, long-lasting friendships, and mutual maker became implantable and redefined for long-term pacing respect." 280 PART IV: DEVICES AND THERAPIES / MCMANUS ET AL.

CARDIAC PACEY~KER

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5. HEART VALVES company; however, he declined because of the demands of his The initial development process in the field of prosthetic clinical practice. Rather, he suggested that Dr. C.W. Lillehei heart valves involved the search for biologically compatible become the medical director, a post that Lillehei held until his materials and hemologically tolerant designs; success could death in 1999 (6). not be achieved without the union of these two factors. At that 6. OTHER UNIVERSITY-AFFILIATED time, there was no satisfactory mechanism to achieve this goal MEDICAL DEVICES scientifically; a trial-and-error method was used. The development of prosthetic heart valves became the purview of numer- Many of the major breakthroughs in cardiac device develop- ous cardiovascular surgeons, who often collaborated with ment at the University of Minnesota occurred in associated engineers; to distinguish one valve from another, each prosthe- collaborations with the Surgery Department. In more recent sis often became identified with the surgeon developer (6). times, several more cardiovascular medical devices have been Lillehei and his colleagues developed four different valves: invented in departments other than the Department of Surgery, (1) a nontilting disk valve called the Lillehei-Nakib Toroidal specifically the Departments of Medicine and Radiology. Sev- Valve in 1967; (2) two tilting disk valves, the Lillehei-Cruz- eral areas of cardiovascular devices are described in the follow- Kaster in 1963 and the Lillehei-Kaster in 1970 (produced by ing sections. Medical Inc. in 1970 and eventually distributed by Medtronic 6.1. Active Compression/Decompression Inc. in 1974); and (3) a bileaflet valve, the Lillehei-Kalke in Cardiopulmonary Resuscitation Devices: 1965 (manufactured by Surgitool [now Medical Engineering Corporation, Racine, WI] in 1968 and used clinically by Dr. The CardioPump ® Lillehei at the New York Cornell Medical Center) (Fig. 12). The CardioPump ® is an active compression/decompression The St. Jude bileaflet valve was designed by Chris Posis, an device for cardiopulmonary resuscitation (CPR). Weighing a industrial engineer who approached Demetre Nicoloff MD, a mere pound and half, it looks like a modified toilet plunger cardiovascular surgeon at the University of Minnesota. This with a pliable cup that fits onto the patient's chest (Fig. 14). It valve had floating hinges located near the central axis of the employs a combination handgrip/pressure gauge instead of a rigid housing as well as an opening to the outer edge of each wooden handle. Manual CPR exerts downward pressure on the leaflet, leaving a small central opening (Fig. 13) (7). Nicoloff chest, but the chest has to reexpand naturally; importantly, the first implanted this valve in October 1977, and it provided the CardioPump can apply pressure in both directions. With this foundation for the beginning of St. Jude Medical Inc. Dr. action, the heart behaves somewhat like a bellows and allows Nicoloff was asked to serve as the medical director of the new blood to be pulled back into the heart and air into the lungs. CHAPTER 20 / HISTORICAL PERSPECTIVES 281

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Fig. 13. St. Judebileafletprosthesisdevelopedin 1976. CourtesyofSt. Fig. 14. CardioPump, an active compression/decompression device Jude Medical. for cardiopulmonary resuscitation. 282 PART IV: DEVICES AND THERAPIES / MCMANUS ET AL.

6.2. Transcatheter Closure Devices for Congenital Heart Defects Transcatheter closure devices are permanent cardiac implants designed to close defects between chambers of the heart. Such devices are self-expanding, self-centering, umbrella-like devices with a design and shape that varies, as does the exact mode of their deployment. These are implanted in the heart, in a cardiac catheterization laboratory, through catheters inserted into either the artery or vein. Transcatheter closure devices are intended to provide a less-invasive alternative to open heart surgery, which has been the standard of care. The first reported use of a transcatheter closure device for an atrial septal defect was in 1976 by T.D. King and N.L. Mills (Tulane University Medical School, New Orleans, LA). Despite two decades of research, early models of the device were not approved for clinical use because of persistent residual leakage, high failure rates, wire fractures, or embolization of the device. Fig. 15. Self-centering transcatheter device called Angel Wings ®. Reprinted from Heart 1998;80:517-521. With permission from the Nevertheless, several University of Minnesota faculty mem- BMJ Publishing Group. bers used their previous experience with these early devices to devise novel closure models in the early 1990s. One such enhancement was Angel Wings ®(Microvena Corp., White Bear Lake, MN), a transcatheter atrial septal defect closure device designed in 1993 by Gladwin Das MD, an interventional cardiologist in the Department of Medicine (Car- diovascular Division) (9). This device is a self-centering, nitrinol-polyester prosthesis with two square-shape disks and a customized delivery catheter (Fig. 15). The implantation success rate for such closures was 97% for patients with patent foramen ovale and 100% for patients with atrial septal defects in phase II trials, 86% of these patients had zero or 1-mm shunts, and 14% had 1-2-mm shunts. The device was subsequently modified to have two circular disks and to make it retrievable into the delivery catheter and repositionable. The Angel Wings II device is anticipated to enter clinical trials in the near future. 6.3. Amplatzer ® Family of Occlusion Devices Radiologist Kurt Amplatz MD, from the Department of Radiology at the University of Minnesota, has designed a family of occlusion devices. All Amplatzer ® occlusion devices (AGA Medical Corp., Golden Valley, MN) are preformed"bas- kets" of wire that resume their preformed mushroomlike shapes when extruded from the catheter sheaths (Fig. 16). The cur- Fig. 16. One of the numerous Amplatzer occlusion devices. rently used wire is made from a special alloy of nickel and titanium (Nitinol) that does not break, accepts growth of cardiac endothelial tissue lining, and is absorbed into the heart's septal wall. More recent versions include specialized Dacron fibers, which are contained within the basket component of the device and immediately stop flow. The position of the device is checked Dr. Keith Lurie, from the Department of Medicine (Division by echocardiography and fluoroscopy prior to patient release of Cardiovascular Medicine), and his colleagues outside the (see Chapter 29). university designed this device and licensed it through a Dan- 7. FOOD AND DRUG ADMINISTRATION ish company, Ambu Inc. (Linthicum, MD). It is now considered the first line of therapy for standard CPR and could REGULATES MEDICAL DEVICES improve a person's chance of survival and minimize neurologi- Earl Bakken believed in the "ready, fire, aim" method of cal impairment; it has been shown to extend the 1-year survival device development, which was symbolic of the approach in rate by 10-40%, as indicated in a comparative study of standard which devices were actually tested in humans; therefore, the CPR and active compression/decompression resuscitation for transition from bench to bedside was at an accelerated pace (5). out-of-hospital cardiac arrest (8). However, dramatic changes in the regulation of medical device CHAPTER 20 / HISTORICAL PERSPECTIVES 283 development and use since 1976 have played an important role cal and biotechnology companies; and service and consulting in the number and types of devices manufactured, as well as the organizations. safety of these devices, before clinical use. Medical Alley's primary goals are to: (1) promote greater In 1976, the Medical Device Amendments to the Federal interest and investment in the region's health care-related Food, Drug, and Cosmetic Act established three regulatory research and innovation; (2) focus on legislative issues impor- classes for medical devices based on the degree of control nec- tant to its membership; (3) provide members with educational essary to ensure the safety and effectiveness of various types of opportunities that address current issues and trends affecting devices. The most regulated class is class III devices, which are the health care industry; and (4) assemble leaders from across designed to support or sustain human life or are of substantial the industry to solve industrywide problems in health care. importance in preventing impairment of human health or For example, in 2001, Medical Alley announced a structural present a potential unreasonable risk of illness or injury. All change that launched two "spin-off organizations"--Alley devices placed in class III are subject to premarket approval Institute and Alley Ventures. Alley Institute is a nonprofit orga- requirements, including a scientific review, to ensure their nization that was created to impact and grow the business, work- safety and effectiveness. force, and health care activities of the region directly. As a Under Medical Device Reporting in the Food and Drug 501(c)(3) organization, Alley Institute can receive local and Administration (FDA), all manufacturers, importers, and user national foundation grants; it is also a conduit of Small Business facilities are required to report adverse events and to correct Administration (and Small Business Innovation Research) them quickly. Although, since 1984, manufacturers and import- grants for small and emerging medical technology companies. ers of medical devices have been required to report all device- A sample of the projects launched thus far includes related deaths, serious injuries, and certain malfunctions to • MAC-CIM (Medical Alley's Consumer-Coverage Interface the FDA, numerous reports show underreporting. Therefore, Model)--Designing and alpha testing of a process to use the Safe Medical Devices Act (SMDA) of 1990 was imple- peoples' personal values to design their health care coverage mented; device user facilities must report device-related benefits. deaths to the FDA and the manufacturer. In addition, the • Minnesota Partnership for End of Life Care--Working SMDA requires that device user facilities submit reports to the together with Blue Cross and Blue Shield of Minnesota, FDA on an annual basis (FDA Modernization Act of 1998). In HealthPartners, Allina, and Fairview to manage a grant spite of this strict regulatory environment, Minnesota has focused on improving health care at the end of life. continued to be a leading state for design, licensing, and manu- • Class in a BoxZM--Partnering with WomenVenture to bring facture of medical devices. innovative tools and materials directly to seventh and eighth graders in their classrooms, a project designed to get kids 8. MEDICAL ALLEY excited about the wide variety of careers in health care. Spurred by the flurry from Minnesota inventors of innova- • Managing small medical technology companies--Along with tions such as the pacemaker, bubble oxygenator, and artificial the University of St. Thomas, in St. Paul, Minnesota, develop- heart valve, Medical Alley was founded in 1984 as a nonprofit ing an 11-week mini-MBA course in medical technology man- trade association to support the region's growing health care agement. The faculty includes Medical Alley members who industry. Medical Alley was considered to denote the rich geo- provide real-world experience. graphic area of health care-related organizations that extended A for-profit organization, Alley Ventures was designed to from Duluth through Minneapolis/St. Paul and further south to provide seed and early stage capital funding for small and Rochester (see www.medicalalley.org). More recently, Medical emerging companies in the areas of medical devices, bioscience, Alley has expanded beyond the Minnesota border into Canada, life sciences, and health care. In addition to providing financial Wisconsin, Iowa, Illinois, and the Dakotas. This expanded ter- support (currently in the range of $50,000-$1,000,000), Alley ritory is home to over 800 medical device manufacturers and Ventures also offers assistance in management as well as clini- thousands of health care-related organizations, making it one of cal, engineering, and governing board expertise. the highest concentrations of businesses in this industry in the Furthermore, Medical Alley is active in state legislative lob- world. bying, with a government committee and two legislative con- Medical Alley was founded by Earl Bakken, who pioneered sultants at the state level. The association also participates in the implantable pacemaker business through his company, national advocacy and lobbying activities, for example, work- Medtronic, Inc., in the 1960s. Bakken remains on the Medical ing with US senators and legislators on the Medical Device Alley board of directors to this day, and Don Gerhardt cur- User Fee and Modernization Act of 2002. rently presides as president over the association. Guided by The host ofapprox 80 educational seminars annually, Medi- the mission "to promote an environment to enhance innova- cal Alley promotes interactive learning opportunities at which tion in healthcare," Medical Alley is a Minneapolis-based trade participants can network and discuss current issues, trends, association that currently represents a membership of more and regulations affecting the health care industry; such forums than 300 health care-related companies and organizations. Its are directed primarily to clinical studies, marketing]communi- cohorts include a wide cross-section of medical device, equip- cations activities, regulatory affairs, reimbursement issues, ment, and product manufacturers; health care providers such research and development, and human resources in health care. as hospitals and clinics; health plans and insurance organiza- In 2004, Medical Alley, in collaboration with the University tions; medical education and research facilities; pharmaceuti- of Minnesota's Biomedical Engineering Institute, sponsored its 284 PART IV. DEVICES AND THERAPIES/ MCMANUS ET AL.

Table 3 It has been described that Owen Wangensteen, recognizing Department of Physiology at the University how many such findings were directly applicable to surgery, of Minnesota: Chairs/Interim Heads initiated collaborations with Visscher and the Physiology Physiology department Department. To this extent, Wangensteen even initiated and chair~interim head Position Years served conducted a regular "Physiology-Surgery Conference" that Richard O. Beard Department chair 1889-1913 was considered "invaluable in acquainting surgical residents Elias P. Lyon Department chair 1913-1936 with the techniques of experimental physiology" (12). Many Dr. Maurice B. Visscher Department chair 1936-1968 also credit Wangensteen's academic philosophies for enabling Eugene Grim Department chair 1968-1986 the pioneering advancements in open heart surgery and subse- Richard E. Poppele Interim head 1986-1988 quent pacemaker technologies at the University of Minnesota. Robert F. Miller Department chair 1988-1998 Joseph DiSalvo Interim head 1998-2002 For example, Earl Bakken asked C. Walton Lillehei in 1997, Douglas Wangensteen Interim head 2002-present "How did you have the courage to go ahead with these pioneering-type experiments?" Lillehei replied, "As I think, when I look back, that was part of the Wangensteen training system" (13). He further elaborated: He [Wangensteen] was a unique person in many regards. One [aspect of his] uniqueness was his train- third poster session to showcase the ongoing biomedical engi- ing system. He had a great faith in research, animal or neering research. Graduates shared posters, medical device pro- other types of laboratory research. He felt that the totypes, and bioengineering innovations on topics ranging from results of his research gave the young investigator the tissue engineering to cellular bioengineering, to medical de- courage to challenge accepted beliefs and go forward, vices and diagnostic techniques. This interactive forum allowed which you would not have had, as I look back, as a dialogue and potential collaboration between students and in- young surgical resident. That's why many of the great dustry professionals. universities didn't produce much in the way of innovative research, because they were so steeped in tra- 9. CARDIOVASCULAR PHYSIOLOGY dition. Wangensteen had a wide open mind. If research AT THE UNIVERSITY OF MINNESOTA showed some value then you should pursue it. The Department of Physiology at the University of Minne- The University of Minnesota has a rich history of basic and sota has a rich history of performing basic cardiovascular applied cardiac research. Noted in Table 4 are several of the research and establishing clinical collaborations within the physiologists who had full or adjunct appointments in the Physi- institution. Not only have these individuals published many ology Department and worked on topics relevant to the cardio- important basic research papers, but they also have been inte- vascular system; these physiologists published numerous grally involved in the training of many generations of cardiac papers or served as advisors for numerous theses. Interestingly, physiologists, surgeons, and biomedical engineers. the past few years have brought a renewed interest in refocusing One of the more notable chairs of the Department of Physi- the Physiology Department to again be a leader in the cardio- ology was Maurice Visscher, who was present during the Owen vascular field. For example, the department has embarked on Wangensteen and C. Walton Lillehei eras. In 1936, Dr. Visscher creating novel educational outreach programs for the local car- returned to the University of Minnesota to succeed Dean Lyon diovascular industry and added Professor Doris Taylor to the as the head of physiology (Table 3). He first came to Minnesota faculty as the newly created Medtronic-Bakken Research Chair in 1922 as a graduate student in physiology under the mentorship in Cardiac Repair. of Frederick Scott and satisfied the requirements for both PhD Dr. Lillehei believed that"What mankind can dream, research and MD degrees in a 4-year period (10). and technology can achieve." And, with the support of the Interestingly, subsequent to his studies, Visscher served a Lillehei Heart Institute in collaboration with the Biomedical postdoctoral fellowship in England at the University College, Engineering Institute, the circle has been completed. London. While there, he worked under the advisement of the notable cardiac physiologist Ernest Starling, who at that REFERENCES time was near the end of his brilliant career (e.g., Starling's law 1. Lillehei,C.W. (1994) The birth ofopen-heart surgery:then the golden of the heart). Together in 1927, Starling and Visscher pub- years. Cardiovasc Surg. 2,308-317. lished a classic paper in which, using a heart-lung preparation 2. Lillehei, C.W., Varco, R.L., Cohen, M., Warden, H.E., Patton, C., (introduced by Starling in 1910), they reported that the oxygen and Moller, J.H. (1986) The first open-heart repairs of ventricular septal defect, atrioventricular communis, and tetralogy of Fallot consumption of the heart was correlated directly with its vol- using extracorporeal circulation by cross-circulation. Ann Thorac ume in diastole without regard to the amount of work the heart Surg. 41, 4-21. was exerting in pumping blood (11,12). After Starling's death 3. Lillehei, C.W. (1982) A personalized history of extracorporeal cir- in 1927, Visscher continued his research on this topic while culation. Trans Am Soc Artif lnternal Organs. 28, 5-16. serving as the Physiology Department chair in Minnesota; his 4. Moore, M. (1992) The Genesis of Minnesota's Medical Alley. UMN Medical Foundation Bulletin. Minneapolis Medical Foundation, research was considered to shed valuable light on the mecha- Minneapolis, MN. Winter 1992. nisms underlying heart disease caused by coronary occlusion, 5. Rhees, D. and Jeffrey, K. (2000) Earl Bakken's little white box: the in general. complex meanings of the first transistorized pacemaker, in Expos- CHAPTER 20 / HISTORICAL PERSPECTIVES 285

Table 4 Selected Theses From the Department of Physiology at the University of Minnesota: Theses Related to Cardiovascular Physiology Investigators Era Topics Maurice Visscher 1920s to 1930s Coronary blood flow, oxygen delivery rate, and cardiac performance; autoregulation of coronary blood flow; medical research and ethics Mead Cavert 1970s to 1980s Clinical cardiology Marvin Bacaner 1960s to 1990s Antiarrhythmic, antifibrillatory, and hemodynamic actions of bethanidine sulfate Irwin J, Fox 1970s to 1980s Assessment of regional myocardial blood flows; arterial dilution curves in the study of heart disease Victor Lorber 1950 to 1970s Cellular junctions in the tunicate heart; regulation of energy liberation in the isolated heart Michael Hoey 1980s to 2002 Cardiac ablation Joseph DiSalvo 1990s to present Chronic atrial-ventricular block; properties and function of phosphatases from vascular smooth muscle Steven Katz 1990s to present The renin/angiotensinsystem and the failing heart Paul Iaizzo 1990s to present Intercardiac imaging within large mammalian isolated hearts; cardiac devices; isolated human trabeculae Robert Bache 2000s to present Cardiac energetics John Osborn 1990s to present Autonomic response and the cardiovascular system; pathophysiology of hypertension Scott O'Grady 1990s to present Electrolyte transport in epithelia Doris Taylor 2003 to present Cardiac repair and regeneration

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