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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-AFFILIATED MEDICAL DEVICES

FOOD AND DRUG ADMINISTRATION REGULATES MEDICAL DEVICES MEDICAL ALLEY

CARDIOVASCULAR PHYSIOLOGY AT THE UNIVERSITY OF MINNESOTA REFERENCES

1. INTRODUCTION

The era from 1950 to 1967 was an incredible time of innovation within the University of Minnesota's Department of Surgery in the newly emerging field of open heart surgery.

There were many reasons for this, but most importantly it was attributable to the following: (1) the university had excellent facilities, including a unique privately funded 80-bed heart hospital for pediatric and adult patients, and (2) the Depart- ment of Surgery was led by a chair, Owen H. Wangensteen, MD, who "created the milieu and the opportunities for great achievements by many of his pupils," and was considered the

"mentor of a thousand surgeons" (Fig. 1, Table 1) (1).

More specifically, Dr. Wangensteen encouraged his medical students to "step out of the box," look at problems in different ways, and not assume that those who went before them had all the answers. He also believed strongly in collaborations with the basic science departments, specifically the Department of Physiology, with the department head, Maurice Visscher, who From: Handbook of Cardiac Anatomy, Physiology, and Devices Edited by: P. A. Iaizzo © Humana Press Inc., Totowa, NJ

played an integral role in supporting both research and the clinical training of surgical residents. To that end, Wangensteen instituted a 2-year research program for all residents; this surgical PhD program was the only one in the country at its incep- tion, and it still exists today.

An important part of the innovative surge was that many surgical residents were returning from World War II, which had recently provided them with life-and-death situations when managing MASH (mobile army surgical hospital) units--they had little or no fear of death. Their generation was not afraid of

"pushing the envelope" to help patients. By today's standards, they would be viewed as "mavericks" or "cowboys," but in fact they had little to lose, as on the battlefields where they received their early exposure; their patients were dying or had little chance of survival without the novel techniques successfully implemented in Minnesota.

One of these young war-experienced surgeons was C. Walton Lillehei, who returned to the University of Minnesota in 1950 to complete his surgical residency after leading an Army MASH unit in both North Africa and Italy (Fig. 2). Walt, as he was

273

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

Fig. 1. "The Chief," Dr. Owen H. Wangensteen, the youngest Surgery Department chair at age 31 years (chair from 1930 to 1967).

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. 3. Clarence Dennis with the first heart-lung machine at the Uni- versity of Minnesota.

Fig. 2. Walt Lillehei in Army uniform.

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 York City (I).

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CHAPTER 20 / HISTORICAL PERSPECTIVES 275

Table 2

University of Minnesota Milestones

1911 1930s 1950 1951 1952 1953 1954 1954 1955 1958 1963 1966 1966-1968

1887 New standards requiring medical students to pass exams and gain medical examining board approval (led by Medical School Dean Perry Millard)

Minnesota became the first state to mandate hospital internships for medical students Discovery of link between cholesterol and heart disease (Ancel Keys)

First adaptation of the mass spectrograph (Alfred Nier) First attempt to use a heart-lung machine (Clarence Dennis)

First successful open heart surgery using hypothermia (F. John Lewis) First jejunoileal bypass (Richard L.Varco)

First open heart procedure using cross-circulation (C. Walton Lillehei) First surgical correction of tetralogy of Fallot (C. Walton Lillehei) First successful use of the bubble oxygenator (Richard DeWall) First use of a small, portable, battery-powered pacemaker (Earl Bakken) First human partial ileal bypass (Henry Buckwald)

First clinical pancreas transplant (William D. Kelly and Richard C. Lillehei)

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 h y p o t h e r m i a 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 b o d y ' 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 M a y 6, 1953, when Dr. J.

Gibbon closed an atrial septal defect using a pump oxygenator for an intracardiac operation. Although this first success with the pump oxygenator was well received, it aroused surprisingly

Fig. 4. In this 1952 photo, Richard L. Varco (left) and F. John Lewis stand behind the hypothermia machine that they used during the world's first successful open heart surgery.

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276 PART IV: DEVICES AND THERAPIES / MCMANUS ET AL.

Fig. 5. Diagram of cross-circulation.

little excitement or enthusiasm among cardiologists and cardiac surgeons at that time, likely because other centers had launched their own experiments with bubble oxygenators.

Interestingly, Gibbon was never able to repeat his one clinical success; he ultimately became discouraged and did not use the pump oxygenator again.

There was a common scenario, namely, good results with acceptable survival in the experimental animals but nearly universal faihu'e when the same appara- tus and techniques were applied to human beings.

Thus, many of the most experienced investigators concluded with seemingly impeccable logic that the problems were not with the perfusion techniques or the heart lung machines. Rather, they came to believe that the "sick human heart" ravaged by failure, could not possibly be expected to tolerate the magnitude of the operation required and then recover with good output, as occurred when the same machines and techniques were applied to healthy dogs. Thus, dis- couragement and pessimism about the future of open heart surgery was widespread. (2)

2. CROSS-CIRCULATION

Extracorporeal circulation by controlled cross-circulation was introduced clinically on March 26, 1954 (Fig. 5). The use of cross-circulation for intracardiac operations was an immense departure from established surgical practice at the time and was the major breakthrough that motivated innovations in the area of open heart surgery (3). The thought of taking a normal healthy human being into the operating room to provide donor circula-

tion was considered unacceptable and even immoral by some critics. The risks to the donors were: (1) blood incompatibility, (2) infection, (3) air embolism, and (4) blood volume imbal- ance. Regardless, Lillehei and his team completed 45 such operations between 1954 and 1955. In early 1955, three addi- tional bypass methods were introduced and successfully employed, including: (1) perfusion from a reservoir of arterialized blood, (2) heterologous (dog) lungs as an oxygenator, and (3) the DeWall-Lillehei disposable bubble oxygenator (2).

The likely single most important discovery that contributed to the success of clinical open heart operations was the realiza- tion of the vast discrepancy between the total body flow rate thought necessary and what was actually necessary. Lillehei and his team are credited with applying the findings of two British surgeons (A. T. Andreasen and F. Watson) who had identified the azygos factor--the ability of dogs to survive up to 40 rain without brain damage when all blood flow was stopped except through the azygos vein.

Specifically, Morley Cohen and Lillehei hypothesized that when blood flow was low, the blood vessels dilated to receive a larger share of the blood; the tissues absorbed a much higher proportion of the oxygen compared to normal circulation. Pre- viously, it was thought that basal or resting cardiac output at 100-160 mL/kg/min was the required safe maintenance during cardiopulmonary bypass. In contrast, the azygos flow studies showed that 8-14 mL/kg/min maintained the physiological integrity of the vital centers, but Lillehei added a margin of safety and set his basic perfusion rate at 25-30 mL/kg/min. This approach reduced excessive complications of blood loss, excessive hemolysis, abnormal bleeding, and renal shutdown (2).

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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 did not perform surgery, they would travel to the Mayo Clinic 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. L I L L E H E I - D E W A L L BUBBLE O X Y G E N A T O R

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 oxygenators were (1) poor efficiency, (2) excessive hemolysis, (3) large 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 hemolytic solutions, reassembled, resterilized, and reconfig- ured.

During this era, Richard DeWall came to work at the Univer- sity of Minnesota, initially, as an animal attendant in Lillehei's research lab. DeWall would manage the pump while the anes- thesiologists would take breaks, and soon he began to take an interest in the problems associated with oxygenating blood.

Eventually, Lillehei challenged DeWall to find a way to elimi- nate bubbles in the procedure. Subsequently, DeWall produced

Fig. 6. Mayo Clinic's heart-lung machine was as big as a Wurlitzer organ; it cost thousands of dollars and required great skill to operate.

Fig. 7. University of Minnesota' s bubble oxygenator cost $15 and was easy to use. Richard DeWall is shown here with his model in 1955.

a huge technological breakthrough in 1955 by developing a bubble oxygenator with a unique method for removing bubbles from the freshly oxygenated blood (Fig. 7). In DeWall's design, blood entered the bottom of a tall cylinder along with oxygen passed through sintered glass to create bubbles. As the bubbles and blood rose, gas exchange occurred at the surface of each bubble. At the top of the cylinder, arterialized bubble-rich blood passed over stainless steel wool coated with silicone antifoam;

it then traveled through a long helical settling coil to allow bubbles to rise slowly and exit the blood.

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278 PART IV: DEVICES AND THERAPIES / MCMANUS ET AL.

Fig. 8. Richard DeWall and Vince Gott look at the first commercially manufactured sterile bubble oxygenator in 1956.

Two important components in the Lillehei-DeWall bubble oxygenator were the tubing and the silicon antifoam solution.

The tubing was Mayon polyethylene tubing (typically used in the dairy industry and in the production of mayonnaise), avail- able from Mayon Plastics (Hopkins, MN), with a company chief executive officer who was a classmate of Lillehei's and a graduate of the university's chemical engineering program. The silicone antifoam solution, Antifoam A, was used to coat the tubing to prevent foaming of the liquids transported.

The oxygenator was wonderfully efficient; animals (and later patients) did not show detectable effects of residual gas emboli.

More important, this design eventually led to the development of a plastic, prepackaged, disposable, sterile oxygenator that replaced the expensive stainless steel, labor-intensive screen, and film devices. An economic and reliable oxygenator had arrived, and the medical industry began to use disposable components for the heart-lung machine.

Two years after its introduction, the DeWall-Lillehei bubble oxygenator had been used in 350 open heart operations at the University of Minnesota. DeWall steadily improved the device through three generations of models, but it remained a very simple, disposable, and heat-sterilizable device that could be built to accommodate only the amount of blood required for each patient and then discarded.

In 1956, another one of Lillehei's residents, Vincent Gott, invented a bubble oxygenator in which DeWall's helix design was flattened and enclosed between two heat-sealed plastic sheets (Fig. 8). This sheet bubble oxygenator proved to be the key to subsequent widespread acceptance of the device for open heart surgery because it could be easily manufactured and distributed in a sterile package; it was inexpensive enough to be disposable. The University of Minnesota licensed rights to manufacture and sold the device to Travenol Inc. (Minneapolis, MN). With the bubble oxygenator and techniques developed by Lillehei and his colleagues, the University of Minnesota had become prominent for the making open heart surgery possible and relatively safe (4).

4. HEART BLOCK A N D 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 chest, there were no 30-day survivors.

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 incredibly painful for children and typically left scarring and/or blisters. In addition, it used an alternating current electrical source, limiting the mobility of the patient to the length of the cord. Spurred by such adversity, Lillehei and his research team found, in 1956, that an electrode directly connected to the ventricular muscle from a pulse generator producing repetitive electrical stimuli of small magnitude (5-10 mA) provided very effective control of the heart rate and an 89% survival rate for patients with prior heart block.

On January 30, 1957, a pacemaker lead made ofa multistrand, braided stainless steel wire in a Teflon sleeve was implanted into a patient's ventricle myocardium, with the other end brought through the surgical wound and attached to external stimulation. The utilized pacemaker (pulse generator) was a Grass physiological stimulator borrowed from the university's Physiology Department. This procedure was designed for short- term pacing, with removal of the wires 1-2 weeks after the patient's heart had regained a consistent rhythm.

Following near disaster for a pacemaker-dependent patient when the electrical service failed in the University hospital because of a storm, Lillehei asked his medical equipment repairman, Earl Bakken, to design a battery-powered, wearable pacemaker to improve the patient's mobility (Fig. 9). This Bakken did, using a circuit modified from a diagram for a transistorized metronome in Popular Electronics magazine as a model (Fig. 10); a few months later, such as device was used clinically on April 14, 1958.

Bakken's transistor pulse generator made a miraculous

"overnight" transition from bench testing to clinical use; this invention then set the stage for creation of the cardiac pacing industry. For the next decade or so, it would become common practice to put new devices or prototypes (even fully implantable ones) into clinical use immediately and then iron out the imperfections based on the accumulation of clinical experiences. This humanitarian practice developed because most of the early patients were close to death, and no other treatments existed (5). Eventually, Medtronic, Inc. (Minneapolis, MN),

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

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under B akken's leadership, became the world's leading manu- facturer of cardiac pacemakers, beginning with the Model 5800.

The first generation of the 5800 pacemaker was black, but was quickly changed to white to look cleaner and more sanitary (Fig. 11). Between 1959 and 1964, only a few hundred pace- makers were sold because of the reusability of this system and the short-term postsurgery focus; orders soared once the pace- maker became implantable and redefined for long-term pacing

use. Nevertheless, the 5800 pacemaker became the symbol for Medtronic's shared belief in medical progress through technol- ogy; this was celebrated during an unveiling, at his retirement celebration in 1994, of a bronze statue of Earl Bakken holding the 5800 pacemaker. Years later, the 5800 was viewed by Lillehei as a technological watershed: "It was the fruit of inter- disciplinary collaboration, exemplifying the marriage of medi- cine and technology, long-lasting friendships, and mutual respect."

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2 8 0 PART IV: DEVICES A N D THERAPIES / M C M A N U S ET AL.

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5. HEART VALVES

The initial development process in the field of prosthetic heart valves involved the search for biologically compatible materials and hemologically tolerant designs; success could not be achieved without the union of these two factors. At that time, there was no satisfactory mechanism to achieve this goal scientifically; a trial-and-error method was used. The development of prosthetic heart valves became the purview of numerous cardiovascular surgeons, who often collaborated with engineers; to distinguish one valve from another, each prosthesis often became identified with the surgeon developer (6).

Lillehei and his colleagues developed four different valves:

(1) a nontilting disk valve called the Lillehei-Nakib Toroidal Valve in 1967; (2) two tilting disk valves, the Lillehei-Cruz- Kaster in 1963 and the Lillehei-Kaster in 1970 (produced by Medical Inc. in 1970 and eventually distributed by Medtronic Inc. in 1974); and (3) a bileaflet valve, the Lillehei-Kalke in 1965 (manufactured by Surgitool [now Medical Engineering Corporation, Racine, WI] in 1968 and used clinically by Dr.

Lillehei at the New York Cornell Medical Center) (Fig. 12).

The St. Jude bileaflet valve was designed by Chris Posis, an industrial engineer who approached Demetre Nicoloff MD, a cardiovascular surgeon at the University of Minnesota. This valve had floating hinges located near the central axis of the rigid housing as well as an opening to the outer edge of each leaflet, leaving a small central opening (Fig. 13) (7). Nicoloff first implanted this valve in October 1977, and it provided the foundation for the beginning of St. Jude Medical Inc. Dr.

Nicoloff was asked to serve as the medical director of the new

company; however, he declined because of the demands of his clinical practice. Rather, he suggested that Dr. C.W. Lillehei become the medical director, a post that Lillehei held until his death in 1999 (6).

6. OTHER UNIVERSITY-AFFILIATED MEDICAL DEVICES

Many of the major breakthroughs in cardiac device development at the University of Minnesota occurred in associated collaborations with the Surgery Department. In more recent times, several more cardiovascular medical devices have been invented in departments other than the Department of Surgery, specifically the Departments of Medicine and Radiology. Sev- eral areas of cardiovascular devices are described in the following sections.

6.1. Active Compression/Decompression Cardiopulmonary Resuscitation Devices:

The CardioPump ®

The CardioPump ® is an active compression/decompression device for cardiopulmonary resuscitation (CPR). Weighing a mere pound and half, it looks like a modified toilet plunger with a pliable cup that fits onto the patient's chest (Fig. 14). It employs a combination handgrip/pressure gauge instead of a wooden handle. Manual CPR exerts downward pressure on the chest, but the chest has to reexpand naturally; importantly, the CardioPump can apply pressure in both directions. With this action, the heart behaves somewhat like a bellows and allows blood to be pulled back into the heart and air into the lungs.

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282 PART IV: DEVICES A N D THERAPIES / MCMANUS ET AL.

Fig. 15. Self-centering transcatheter device called Angel Wings ®.

Reprinted from Heart 1998;80:517-521. With permission from the BMJ Publishing Group.

Fig. 16. One of the numerous Amplatzer occlusion devices.

Dr. Keith Lurie, from the Department of Medicine (Division of Cardiovascular Medicine), and his colleagues outside the university designed this device and licensed it through a Dan- ish company, Ambu Inc. (Linthicum, MD). It is now considered the first line of therapy for standard CPR and could improve a person's chance of survival and minimize neurologi- cal impairment; it has been shown to extend the 1-year survival rate by 10-40%, as indicated in a comparative study of standard CPR and active compression/decompression resuscitation for out-of-hospital cardiac arrest (8).

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.

Nevertheless, several University of Minnesota faculty members 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 currently 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 by echocardiography and fluoroscopy prior to patient release (see Chapter 29).

7. FOOD A N D DRUG ADMINISTRATION REGULATES MEDICAL DEVICES

Earl Bakken believed in the "ready, fire, aim" method of device development, which was symbolic of the approach in which devices were actually tested in humans; therefore, the transition from bench to bedside was at an accelerated pace (5).

However, dramatic changes in the regulation of medical device

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development and use since 1976 have played an important role in the number and types of devices manufactured, as well as the safety of these devices, before clinical use.

In 1976, the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act established three regulatory classes for medical devices based on the degree of control necessary to ensure the safety and effectiveness of various types of devices. The most regulated class is class III devices, which are designed to support or sustain human life o r are of substantial importance in preventing impairment of human health o r

present a potential unreasonable risk of illness or injury. All devices placed in class III are subject to premarket approval requirements, including a scientific review, to ensure their safety and effectiveness.

Under Medical Device Reporting in the Food and Drug Administration (FDA), all manufacturers, importers, and user facilities are required to report adverse events and to correct them quickly. Although, since 1984, manufacturers and importers of medical devices have been required to report all device- related deaths, serious injuries, and certain malfunctions to the FDA, numerous reports show underreporting. Therefore, the Safe Medical Devices Act (SMDA) of 1990 was implemented; device user facilities must report device-related deaths to the FDA and the manufacturer. In addition, the SMDA requires that device user facilities submit reports to the FDA on an annual basis (FDA Modernization Act of 1998). In spite of this strict regulatory environment, Minnesota has continued to be a leading state for design, licensing, and manufacture of medical devices.

8. M E D I C A L A L L E Y

Spurred by the flurry from Minnesota inventors of innovations such as the pacemaker, bubble oxygenator, and artificial heart valve, Medical Alley was founded in 1984 as a nonprofit trade association to support the region's growing health care industry. Medical Alley was considered to denote the rich geo- graphic area of health care-related organizations that extended from Duluth through Minneapolis/St. Paul and further south to Rochester ( s e e www.medicalalley.org). More recently, Medical Alley has expanded beyond the Minnesota border into Canada, Wisconsin, Iowa, Illinois, and the Dakotas. This expanded ter- ritory is home to over 800 medical device manufacturers and thousands of health care-related organizations, making it one of the highest concentrations of businesses in this industry in the world.

Medical Alley was founded by Earl Bakken, who pioneered the implantable pacemaker business through his company, Medtronic, Inc., in the 1960s. Bakken remains on the Medical Alley board of directors to this day, and Don Gerhardt currently presides as president over the association. Guided by the mission "to promote an environment to enhance innovation in healthcare," Medical Alley is a Minneapolis-based trade association that currently represents a membership of more than 300 health care-related companies and organizations. Its cohorts include a wide cross-section of medical device, equipment, and product manufacturers; health care providers such as hospitals and clinics; health plans and insurance organizations; medical education and research facilities; pharmaceuti-

cal and biotechnology companies; and service and consulting organizations.

Medical Alley's primary goals are to: (1) promote greater interest and investment in the region's health care-related research and innovation; (2) focus on legislative issues important to its membership; (3) provide members with educational opportunities that address current issues and trends affecting the health care industry; and (4) assemble leaders from across the industry to solve industrywide problems in health care.

For example, in 2001, Medical Alley announced a structural change that launched two "spin-off organizations"--Alley Institute and Alley Ventures. Alley Institute is a nonprofit organization that was created to impact and grow the business, work- force, and health care activities of the region directly. As a 501(c)(3) organization, Alley Institute can receive local and national foundation grants; it is also a conduit of Small Business Administration (and Small Business Innovation Research) grants for small and emerging medical technology companies.

A sample of the projects launched thus far includes

• MAC-CIM (Medical Alley's Consumer-Coverage Interface Model)--Designing and alpha testing of a process to use peoples' personal values to design their health care coverage benefits.

• Minnesota Partnership for End of Life Care--Working together with Blue Cross and Blue Shield of Minnesota, HealthPartners, Allina, and Fairview to manage a grant focused on improving health care at the end of life.

• Class in a BoxZM--Partnering with WomenVenture to bring innovative tools and materials directly to seventh and eighth graders in their classrooms, a project designed to get kids excited about the wide variety of careers in health care.

• Managing small medical technology companies--Along with the University of St. Thomas, in St. Paul, Minnesota, developing an 11-week mini-MBA course in medical technology management. The faculty includes Medical Alley members who provide real-world experience.

A for-profit organization, Alley Ventures was designed to provide seed and early stage capital funding for small and emerging companies in the areas of medical devices, bioscience, life sciences, and health care. In addition to providing financial support (currently in the range of $50,000-$1,000,000), Alley Ventures also offers assistance in management as well as clinical, engineering, and governing board expertise.

Furthermore, Medical Alley is active in state legislative lobbying, with a government committee and two legislative con- sultants at the state level. The association also participates in national advocacy and lobbying activities, for example, working with US senators and legislators on the Medical Device User Fee and Modernization Act of 2002.

The host ofapprox 80 educational seminars annually, Medi- cal Alley promotes interactive learning opportunities at which participants can network and discuss current issues, trends, and regulations affecting the health care industry; such forums are directed primarily to clinical studies, marketing]communi- cations activities, regulatory affairs, reimbursement issues, research and development, and human resources in health care.

In 2004, Medical Alley, in collaboration with the University of Minnesota's Biomedical Engineering Institute, sponsored its

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284 PART IV. DEVICES AND THERAPIES / MCMANUS ET AL.

Table 3

Department of Physiology at the University of Minnesota: Chairs/Interim Heads Physiology department

chair~interim head Position Years served Richard O. Beard Department chair 1889-1913 Elias P. Lyon Department chair 1913-1936 Dr. Maurice B. Visscher Department chair 1936-1968 Eugene Grim Department chair 1968-1986 Richard E. Poppele Interim head 1986-1988 Robert F. Miller Department chair 1988-1998 Joseph DiSalvo Interim head 1998-2002 Douglas Wangensteen Interim head 2002-present

third poster session to showcase the ongoing biomedical engineering research. Graduates shared posters, medical device prototypes, and bioengineering innovations on topics ranging from tissue engineering to cellular bioengineering, to medical devices and diagnostic techniques. This interactive forum allowed dialogue and potential collaboration between students and industry professionals.

9. C A R D I O V A S C U L A R P H Y S I O L O G Y A T T H E U N I V E R S I T Y O F M I N N E S O T A

The Department of Physiology at the University of Minne- sota has a rich history of performing basic cardiovascular research and establishing clinical collaborations within the institution. Not only have these individuals published many important basic research papers, but they also have been inte- grally involved in the training of many generations of cardiac physiologists, surgeons, and biomedical engineers.

One of the more notable chairs of the Department of Physi- ology was Maurice Visscher, who was present during the Owen Wangensteen and C. Walton Lillehei eras. In 1936, Dr. Visscher returned to the University of Minnesota to succeed Dean Lyon as the head of physiology (Table 3). He first came to Minnesota in 1922 as a graduate student in physiology under the mentorship of Frederick Scott and satisfied the requirements for both PhD and MD degrees in a 4-year period (10).

Interestingly, subsequent to his studies, Visscher served a postdoctoral fellowship in England at the University College, London. While there, he worked under the advisement of the notable cardiac physiologist Ernest Starling, who at that time was near the end of his brilliant career (e.g., Starling's law of the heart). Together in 1927, Starling and Visscher published a classic paper in which, using a heart-lung preparation (introduced by Starling in 1910), they reported that the oxygen consumption of the heart was correlated directly with its volume in diastole without regard to the amount of work the heart was exerting in pumping blood (11,12). After Starling's death in 1927, Visscher continued his research on this topic while serving as the Physiology Department chair in Minnesota; his research was considered to shed valuable light on the mecha- nisms underlying heart disease caused by coronary occlusion, in general.

It has been described that Owen Wangensteen, recognizing how many such findings were directly applicable to surgery, initiated collaborations with Visscher and the Physiology Department. To this extent, Wangensteen even initiated and conducted a regular "Physiology-Surgery Conference" that was considered "invaluable in acquainting surgical residents with the techniques of experimental physiology" (12). Many also credit Wangensteen's academic philosophies for enabling the pioneering advancements in open heart surgery and subsequent pacemaker technologies at the University of Minnesota.

For example, Earl Bakken asked C. Walton Lillehei in 1997,

"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- ing system. He had a great faith in research, animal or other types of laboratory research. He felt that the results of his research gave the young investigator the courage to challenge accepted beliefs and go forward, which you would not have had, as I look back, as a young surgical resident. That's why many of the great universities didn't produce much in the way of inno- vative research, because they were so steeped in tra- dition. Wangensteen had a wide open mind. I f research showed some value then you should pursue it.

The University of Minnesota has a rich history of basic and applied cardiac research. Noted in Table 4 are several of the physiologists who had full or adjunct appointments in the Physi- ology Department and worked on topics relevant to the cardiovascular system; these physiologists published numerous papers or served as advisors for numerous theses. Interestingly, the past few years have brought a renewed interest in refocusing the Physiology Department to again be a leader in the cardiovascular field. For example, the department has embarked on creating novel educational outreach programs for the local cardiovascular industry and added Professor Doris Taylor to the faculty as the newly created Medtronic-Bakken Research Chair in Cardiac Repair.

Dr. Lillehei believed that"What mankind can dream, research and technology can achieve." And, with the support of the Lillehei Heart Institute in collaboration with the Biomedical Engineering Institute, the circle has been completed.

REFERENCES

1. Lillehei, C.W. (1994) The birth ofopen-heart surgery: then the golden years. Cardiovasc Surg. 2,308-317.

2. Lillehei, C.W., Varco, R.L., Cohen, M., Warden, H.E., Patton, C., and Moller, J.H. (1986) The first open-heart repairs of ventricular septal defect, atrioventricular communis, and tetralogy of Fallot using extracorporeal circulation by cross-circulation. Ann Thorac Surg. 41, 4-21.

3. Lillehei, C.W. (1982) A personalized history of extracorporeal cir- culation. Trans Am Soc Artif lnternal Organs. 28, 5-16.

4. Moore, M. (1992) The Genesis of Minnesota's Medical Alley. UMN Medical Foundation Bulletin. Minneapolis Medical Foundation, Minneapolis, MN. Winter 1992.

5. Rhees, D. and Jeffrey, K. (2000) Earl Bakken's little white box: the complex meanings of the first transistorized pacemaker, in Expos-

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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

Clinical cardiology

Antiarrhythmic, antifibrillatory, and hemodynamic actions of bethanidine sulfate

Assessment of regional myocardial blood flows; arterial dilution curves in the study of heart disease

Cellular junctions in the tunicate heart; regulation of energy liberation in the isolated heart Cardiac ablation

Chronic atrial-ventricular block; properties and function of phosphatases from vascular smooth muscle

The renin/angiotensin system and the failing heart

Intercardiac imaging within large mammalian isolated hearts; cardiac devices; isolated human trabeculae

Cardiac energetics

Autonomic response and the cardiovascular system; pathophysiology of hypertension Electrolyte transport in epithelia

Cardiac repair and regeneration Mead Cavert 1970s to 1980s

Marvin Bacaner 1960s to 1990s Irwin J, Fox 1970s to 1980s

Victor Lorber 1950 to 1970s Michael Hoey 1980s to 2002 Joseph DiSalvo 1990s to present

Steven Katz 1990s to present Paul Iaizzo 1990s to present

Robert Bache 2000s to present John Osborn 1990s to present Scott O'Grady 1990s to present Doris Taylor 2003 to present

ing Electronics (Finn, B., ed. ), Harwood, Amsterdam, The Nether- lands.

6. DeWall, R. ( 2OOO) Evolution of mechanical heart valves.Ann Thorac Surg. 69, 1612-1621.

7. Villafana, M. (1989) It will never work! The St. Jude valve. Ann Thorac Surg. 48, $53-$54.

8. Plaisance, P., Lurie, K.G., Vicaut, E., et al. (1999) A comparison of standard cardiopulmonary resuscitation and active compression- decompression resuscitation for out-of-hospital cardiac arrest.

French Active Compression-Decompression Cardiopulmonary Resuscitation Study Group. N Engl J Med. 341,569-575 9. Das, G.S., Voss, G., Jarvis, G., Wyche, K., Gunther, R., and Wilson,

R.F. (1993) Experimental atrial septal defect closure with a new transcatheter, self-centering device. Circulation. 88, 1754-1764.

10. Visscher, M.B. (1969) A half century in science and society. Annu Rev Physiol. 31, 1-18.

11. Starling, E.H. and Visscher, M.B. (1927) The regulation of the energy output of the heart. J Physiol Lond. 62, 243-261.

12. Wilson, L.G. (ed.) (1989) Medical Revolution in Minnesota: A His- tory of the University of Minnesota Medical School. Midewiwin Press, St. Paul, MN.

13. Rees, D. (interviewer) (2002) Pioneers of the Medical Device Indus- try in Minnesota: An Oral History Project, Earl E. Bakken and Dr.

C. Walton Lillehei. Minnesota Historical Society Oral History Of- rice, St. Paul, MN.

SOURCES

Medical Alley Website: (www.medicalalley.org).

Rigby, M. (1999) The era of transcatheter closure of atrial septal defects.

Heart. 81,227-228.

Stephenson, L. (ed.) (1999) State of the Heart: The Practical Guide to Your Heart and Heart Surgery. Write Stuff Syndicate, Fort Lauder- dale, FL.

US Food and Drug Administration, Center for Devices and Radiological Health. Website: (www.fda.gov/cdrh]pmapage.html).