(Circulation. 1996;93:1621-1629.)
© 1996 American Heart Association, Inc.
Articles |
Angioplasty From Bench to Bedside to Bench
From the Andreas Gruentzig Cardiovascular Center, Emory University, Atlanta, Ga.
Correspondence to Spencer B. King III, MD, Andreas Gruentzig Cardiovascular Center, Emory University Hospital, 1364 Clifton Rd, Suite F606, Atlanta, GA 30322.
Key Words: angioplasty • coronary disease • revascularization • balloon
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Introduction |
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 Top Introduction Prelude to AngioplastyProgress in the 1980sNew Technologies of the...The FutureReferences |
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The patient, a 42-year-old accountant, was suddenly aware of a severe pressure in his midchest. On arrival at the hospital, the pain seemed even more intense, and the ECG confirmed a large, anterior myocardial infarction. In the laboratory, the anterior descending artery was occluded for a few minutes—then open—then the pain was gone! Technical problems of a torn artery were repaired without further pain with the help of a metal supporting stent. Four days later, the patient's question as he walked out of the hospital was, "When can I return to work?"
This is the way it is, but it's not the way it was. How did we arrive at this happy ending that is so common today?
Some say that coronary interventions were inevitable and were the natural progression of our expanding knowledge of vascular disease, but it did not happen that way. The development of angioplasty in all its forms (balloons, stents, ablative devices, and other devices) had a single catalyst, but there were many who added reagents to keep the reaction going. Andreas Gruentzig made interventional cardiology possible, and his is a most interesting story.
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Prelude to Angioplasty |
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TopIntroductionPrelude to AngioplastyProgress in the 1980sNew Technologies of the...The FutureReferences |
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Gruentzig would not have developed angioplasty were it not for the pioneers who went before him. Although Forssmann was called one of the least intellectual to win the Nobel prize, his persistence in the face of adversity was a characteristic shared by Gruentzig. Forssmann's landmark placement of catheters in his own heart1 achieved very little practical use until World War II, when Cournand and others2 3 developed catheter techniques to measure cardiac output during shock states and to deliver drugs centrally. Diagnostic catheterization followed in the late 1940s and 1950s, paving the way for Sones, a trained pediatrician, to appreciate the potential for diagnostic coronary arteriography after a catheterization laboratory accident. Sones's inadvertent injection of the coronary artery was followed by a lifelong dedication to the improvement and safe application of coronary arteriography, without which direct coronary surgery would not have been possible.4 5 The subsequent success of coronary surgery provided the rationale for Gruentzig's concept of coronary endovascular recanalization.
Gruentzig, however, was uniquely prepared for his ultimate destiny by others who pursued a parallel track. Dotter began revascularization of peripheral arteries by successive passage of coaxial catheters into large peripheral arteries.6 Partly because of Dotter's take-it-or-leave-it attitude, combined with a vigorous opposition to the technology by surgeons, there was little acceptance of the technique in the United States. In Europe, however, peripheral vascular disease therapy was, to a greater degree, the purview of nonsurgical specialists. Zeitler, a radiologist from Nuremberg, Germany, had adopted the procedure and was performing a large volume of cases with good results.7 In Europe, the subspecialty of internal medicine, angiology, was also the subspecialty of a 1969 immigrant to Zurich, Switzerland: Andreas Gruentzig.
The Young Gruentzig
Andreas was born in Dresden, Germany, that cultural metropolis
known as Florence by the River Elbe. In 1940, because of the danger of
war, his parents took Andreas and his older brother, Johannes, to
Rochlitz, a small town about 100 km away, for safety.
Johannes remembers that Rochlitz was occupied in 1945 by American troops in exchange for a portion of Berlin. The military commander opened his headquarters in the Gruentzigs' house, and they were forced to move out. Their father, missing in action since the last days of the Berlin resistance, was never seen again.
Times remained very hard for the young family, and in 1950, they were taken in by an uncle in Argentina. To obtain better educational opportunities for her children, Charlotta Gruentzig, a most remarkable woman of many talents, returned the family to Germany in 1952 and enrolled Andreas in the Thomas-Gymnasium in Leipzig (Thomoner-Choir, founded by J.S. Bach), where Andreas flourished as one of the best students. Because of the repressive nature of the communist regime in East Germany, Andreas fled Leipzig through Berlin in 1957 to settle with his brother in Heidelberg, where he would complete his formal education.
Training for Discovery
After medical school graduation in Heidelberg in 1964, Gruentzig
completed a rotating internship, followed by a research fellowship in
epidemiology during which he explored
coronary artery disease, and then training in the Ratchow
Clinic in Darnstadt, Germany, in peripheral vascular
disease. Gruentzig related his first exposure to vascular
recanalization in notes developed with the
assistance of Maria Schlumpf and dictated for a book he intended to
write:
It was at this time that my chief invited me to attend an afternoon meeting in Frankfurt. For the first time, I heard Dr. Eberhart Zeitler speaking about peripheral recanalization using Dotter's method. I recall that my chief was very upset that someone would try to attack diseased arteries by forcing catheters into areas of narrowing. He made it clear that he never wanted such a treatment to take place in his hospital. (Unpublished material, 1985.)
After moving to Zurich as a fellow of Dr Bollinger in the angiology department, Andreas demonstrated his penchant for invention by developing a method to measure the one-half relaxation time of the Achilles tendon reflex produced by electrical stimulation to evaluate ischemic limbs. Subsequently, he moved to the department of radiology. Dr Wellauer, the chief of the department, granted Andreas permission to visit Dr Zeitler to observe the Dotter method. Gruentzig mused, "I not only observed the procedure itself during this time but also saw the patients before and after treatment and when they left the hospital. I was very impressed with the improvement in peripheral ankle pressure as measured by ultrasound and by the fact that the patient was able to walk without any claudication after successful catheter treatment." (Unpublished material, 1985.) Gruentzig felt it was time to introduce the method at the University in Zurich. There was an angiology meeting in Lucerne, Switzerland, that Zeitler was attending. Because this was near Zurich, Gruentzig called Zeitler and asked whether he could come to Zurich with his catheters and, if so, Gruentzig would provide a suitable patient. Gruentzig related:
The meeting in Lucerne was well under way when I finally found a patient with a severe stenosis in the proximal superficial femoral artery. He was being studied angiographically for diagnostic purposes. I informed the patient of the new procedure and asked his permission to use this procedure to improve his intermittent claudication. The patient enthusiastically approved it, and I called Zeitler in Lucerne. The demonstration took place in a special laboratory. I assisted Zeitler while ten of our radiological colleagues observed. Everything went as expected until the end of the procedure when we realized that the patient's lower leg had become quite painful and that we had embolized the entire plaque into the popliteal artery. The plaque had lodged at the bifurcation of the lower leg arteries obstructing flow. The radiologists who were skeptical from the very beginning, now had their proof that the method was of no use whatsoever in human beings. (Unpublished material, 1985.)
Nonetheless, Gruentzig persisted with the help of Dr Ake Senning, Chief of Cardiovascular Surgery, and Dr Walter Siegenthaler, Chief of Medicine, and eventually collected his own small series of Dotter cases, working mostly during lunchtime while he was a full-time fellow in internal medicine. In 1974, he entered the Department of Cardiology, headed by Hans Peter Krayenbuhl and Wilhelm Rutishauser. Krayenbuhl was a talented basic researcher who insisted on pure research methods, but Rutishauser was attracted to Gruentzig's more pragmatic genius and assisted his move toward cardiology. Andreas reflected on future applications:
My background in Internal Medicine was most helpful in helping me follow the patient's progress clinically. At that time it was my intention to become a cardiologist and I began to consider application of the technique to the heart. I designed a prospective followup study of the patients treated with the Dotter technique with regular examinations every three months after the procedure in order to begin assessing the long-term patency of these patients. The early results were favorable but from the very beginning I realized the problems and limitations of Dotter's technique. Everyone involved in the method at that time, including Charles Dotter, realized that any application of the dilatation procedure to other areas of the body would require technical changes. (Unpublished material, 1985.)
The Idea of Balloon Angioplasty
Gruentzig had heard of the ideas of Porstmann, who placed a latex
balloon in a slotted angiographic catheter,8 and the
balloon idea was attractive to him. He needed a small-bore catheter
with a distensible segment, but available balloon material only
expanded around the lesion and did not provide the force necessary to
open it. Gruentzig worked evenings in his kitchen with his assistant,
Maria Schlumpf, her husband, Walter, and Michaela, Andreas' wife, and
during those sessions, many versions of the balloon catheter were
designed and built with tiny bits of rubber, thread, and epoxy glue.
The problem was always the same: when distended in a constriction, the
balloon always took on an hourglass appearance without opening the
lesion. The concept evolved to use a sausage-shaped distensible
segment that would not expand over a predetermined size and would
accommodate high pressure.
Gruentzig said:
I spent the next two years contacting manufacturing plants in an
attempt to solve this problem. Especially fruitful was the cooperation
of a factory which produced shoelaces which provided me with silk
meshes which I planned to wrap around the balloon, thus limiting its
outer diameter. I then needed a very thin balloon to insert within the
mesh. It was at that time that I met a retired chemist, Dr. Hopf, a
professor emeritus of chemistry of the junior high school of Zurich. He
introduced me to polyvinyl chloride compounds. I started to experiment
with this material and studied his book on organic chemistry. I
acquired some small thin polyvinyl chloride material used as insulation
for electrical wires. Following the descriptions in his book, I heated
a localized segment of the tubing and applied compressed air pressure
resulting in a localized aneurysm of the tubing. I used a
second outer tubing measuring 4 mm in diameter to confine the diameter
of the segment. After hundreds of experiments, most of which were
performed in my own kitchen, I was able to form a sausage-shaped
distensible segment which I tried to reinforce with the silk mesh. When
I mounted the material on a normal catheter tubing and applied pressure
to distend the aneurysmal segment, I suddenly realized that the
strength of this material was so great that the silk mesh was not
necessary. This was a great breakthrough and enabled me to reduce the
size of the catheter. (Unpublished material, 1985; Fig 1
.)
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Only single-lumen catheter tubing was available, and Andreas was unsuccessful in persuading any catheter company to build a double-lumen catheter. He then resorted to use of a tip occluder. After placement of the catheter, he would remove the guidewire and replace it with a metal occluder pushed by a wire to stop up the distal end of the catheter. A balloon mounted on the catheter could then be inflated through side holes in the balloon. This was a bulky device, with a large step-up in size where the balloon was tied on the catheter. Gruentzig needed a double-lumen catheter, one lumen for the balloon inflation and one for the guide wire, but no double-lumen catheters that would accommodate the guide wire could be found.
Unable to use a double-lumen catheter, he devised a method by which
the PVC tube with the distensible segment was pulled over an
angiographic catheter. The lumen of the angiographic catheter would
accommodate the guide wire and allow contrast material to be injected
for localization, whereas the space between the catheter and the PVC
tubing would be used to inflate the balloon (Fig 2).
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Many people contributed to the development of angioplasty. An early example of the problem of inflating and deflating the balloon through this tight-fitting PVC tubing/angiographic catheter space was recounted by Maria Schlumpf (personal communication, 1995):
Then help came from Mr. Schmidt, a young man who became enthusiastic about Andreas' balloon catheter and he was successful in solving the second lumen problem in an ingenious way. He constructed a tiny plane and he was successful in making a longitudinal groove on the angiographic catheter's outer surface. This was a great step forward. Then a long PVC tubing with the distensible balloon segment on the end was slipped over this angiographic catheter and fixed at the proximal and distal ends. The next step involved development of a Y connector in order to selectively inflate the inner lumen of the angiographic catheter or the lumen of the balloon catheter which was the space between the PVC layer and the angiographic catheter. We tinkered almost one year, until the double lumen catheter was ready for use.
From the Leg to the Heart
The double-lumen catheter was first used in an iliac artery on
January 23, 1975. Success of this method led to early interest in
reducing the size of the catheter so it could be used in the
coronary arteries. After many efforts at the kitchen table with
his collaborators, Maria, Walter, and Michaela, Gruentzig perfected a
catheter small enough for animal work in the coronary arteries.
The first canine coronary artery dilation that used a silk
ligature for a constrictor was performed on September 24, 1975. Walter
Schlumpf continued to assemble the double-lumen catheters from the
grooved angiographic catheter furnished by the Schneider company and
the heat-set PVC tubing balloons that were fabricated in the
Gruentzig kitchen. By 1976, the Schneider Company and the Cook Company
plant in Denmark took over production of the catheter.
(Personal communication from Maria Schlumpf, 1995.)
In November 1976, Andreas came for the first time to the United States
and presented his canine coronary experiments in a
poster session at the 49th Scientific Sessions of the American Heart
Association in Miami Beach, Fla (Fig 3).9
There were positive responses that overwhelmed Andreas, especially from
Drs Martin Kaltenbach and Richard Myler, who would become important
early collaborators in clinical application, and John Abele, who would
do much on the industry side. Most observers of the experiment were
skeptical (including this author). Dr Paul Lichtlen, Chief of
Cardiology at Hanover, Germany, approached me as I was
attending my poster on medical versus surgical treatment of single
proximal left anterior descending disease. He said, "You must see
the exhibit by this man from Zurich in the next aisle." Andreas
stood in the center of a small group. His bushy mustache and ascot
telegraphed his European roots even before he began to speak. He
clearly was convinced that the method would work. Armed with some
knowledge of the pathology of atherosclerosis, I said,
"This will never work," and we parted.
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Next, Andreas wanted to demonstrate that the method could succeed in human atherosclerotic arteries, and therefore he looked for a surgeon willing to let him perform the technique before bypass. The surgeons in Zurich, who feared that opening a stenosis through their arteriotomy site might set up a competitive flow that would jeopardize graft patency, declined. Andreas recalled, "Dr. Elias Hanna, a surgical colleague working with Richard Myler in San Francisco, did not have this fear. Dr. Hanna indicated that his bypass grafts would `always be better than what was accomplished with dilatation.' " (Unpublished material, 1985.)
Several intraoperative dilations were performed to prove their feasibility and to collect the material that came down the artery to look for emboli. After some improvements in guiding catheters, Andreas was ready to attempt coronary angioplasty in patients. He said:
The first patient on whom we attempted dilatation was a case in which coronary vascular surgery was denied. The patient with unstable angina, multivessel disease, mainstem stenosis, referred to the coronary care unit, was presented to me and everyone assured me that attempted dilatation with success would be the proof for the efficacy of this method. I agreed, eager to enter the area of competition with the surgeons. Unfortunately the patient was so diseased that every attempt to puncture the groin arteries failed because of total closures; only the left brachial artery had positive flow to allow the passage of the catheter to the aorta. With this entrance, the catheters were unable to guide the coronary dilatation catheter to the orifice of the left main so that we had to abandon the procedure. The patient died several days after the procedure of a final myocardial infarction. The case taught me that if you start a method, you should start with an ideal case and not with end stage disease and this has been the truth for so many other colleagues being in a similar position later in time. (Unpublished material, 1985.)
Clinical Application
Almost a year went by before the first dilation. The resistance in
Zurich was such that no case subject could be recruited. Richard Myler
suggested that Andreas come to San Francisco to perform the first
angioplasty on one of Myler's patients. Andreas did go, but during his
2-week stay, he could find no suitable patient. Remarkably, however,
during his absence a patient was identified in Zurich. The
38-year-old insurance salesman had a severe proximal left anterior
descending stenosis, suffered angina, and had a positive
exercise stress test. Dr Bernhard Meier, who was caring for the
patient, tells of the first informed consent for coronary
angioplasty:
On September 15, 1977, Andreas Gruentzig and I entered the patient's room to inform him about the planned procedure and to obtain his consent. In an open way, very atypical for that time in Switzerland, he didn't hide anything and told the patient that his procedure had never been done before in the world and that there was a risk of having an emergency bypass operation. It happened that this patient was a very open businessman who already had done some unusual and new things in his life and planned to do more. He didn't hesitate very long. Even the possibility of an emergency bypass operation could not disturb him. Since the coronary angiography, he already expected to have an operation.10
On September 16, 1977, the procedure was performed. Andreas later remembered:
Early in the afternoon at a time when the anesthesiologist and the cardiac surgeon were available and no cardiac procedure was under way in the operating room, the patient came in to our catheterization laboratory and was catheterized in the usual fashion. . . . The Chief of Cardiology, the cardiac surgeon, anesthesiologist, cardiology and radiology fellows were in the recording room to observe the procedure. The guiding catheter was placed in the left coronary orifice and the dilatation catheter was inserted. . . . The left femoral artery was also punctured and a sheath was placed. This was done to have arterial blood available to pump in via a roller pump through the main lumen of the dilatation catheter into the coronary artery to perfuse the myocardium during balloon inflation. This had been shown to be effective for the prevention of acute ischemia during coronary experiments in dogs. . . . I had planned to start the roller pump as soon as the patient would need it. . . . The catheter wedged the stenosis so that there was no antegrade flow and the distal coronary pressure was very low. To the surprise of all of us, no ST elevation, ventricular fibrillation or even extrasystole occurred and the patient had no chest pain. At this moment I decided not to start the coronary perfusion with the roller pump. After the first balloon deflation, the distal coronary pressure rose nicely. Encouraged by this positive response, I inflated the balloon a second time to relieve the residual gradient. Everyone was surprised about the ease of the procedure and I started to realize that my dreams had come true. . . . A few hours after the procedure, the patient phoned a newspaper without my knowledge and wanted to release his story. The reporter came to him but also asked me for further details and I begged him not to destroy me and the method by early advertisement of a procedure which had not proven to be effective at that point in time. I asked him to wait until more experience would have been accumulated.11
The patient remained free of angina and the artery remained open
without restenosis when I recatheterized him at Emory on
September 16, 198712 13 (Fig 4).
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The next case was a result of a call from Dr Martin Kaltenbach, Chief of Cardiology at the Goethe University in Frankfurt, Germany, who asked Andreas to come to dilate a patient with left main stenosis. The calcified artery opened only partially, and elective surgery was done later. The third patient was treated in Zurich for two-vessel disease. Both the right coronary artery and left anterior descending artery were successfully dilated. The fourth patient had a successful left main dilation in Frankfurt.
It was now time for the 50th Scientific Sessions of the AHA, and Andreas had the option to present an update of the canine experiments in an oral session or to report on the first patients treated.14 He decided on the latter course and asked for an early 1-month restudy of the first patient. During the AHA presentation, he showed a summary slide of the first four patients treated. Andreas recounted:
I also showed the slide of the fourth patient with the incredible success of mainstem dilatation and it was during this case that the audience started applauding in the midst of the lecture. I was so surprised that I almost could not proceed with my ten minute presentation. After the lecture, Sones came to me and asked for proof of my results. I invited him to share with me the cineangiogram which I had in my suitcase. We went to the exhibition hall and reviewed the film of this patient together at the booth of one of the exhibitors. (Unpublished material, 1985.)
Expanding the Technique
Understandably, there was immense interest throughout Europe and
especially in America. The first American cases were performed
simultaneously in March 1978 by Myler in San Francisco and
Stertzer in New York. So many people wanted to visit Andreas to observe
the technique that he settled on the idea of a televised
closed-circuit demonstration course during which he would collect
and demonstrate a series of cases. Twenty-eight physicians attended
the first of these courses. Success and failure were met with an
outpouring of emotion, with even the reserved Americans joining in more
European collegial embraces. The last course in Zurich in August 1980
provided the opportunity to invite the pioneers of angioplasty: Dotter,
Sones, Judkins, Amplatz, and Paulin, among others. During the final
spaghetti dinner, high on a mountain above the lake of Zurich, after
too much red wine, torches were passed from Andreas to each of those in
attendance: first to Sones, Dotter, Judkins, and so forth. The
symbolism was obvious and appropriate.
I would like to include a brief note about how Andreas came to America. During the third course in January 1980, Andreas sat by me on a train ride through the Emmenthal Valley to the site of the farewell dinner. He expressed all his frustrations regarding the limitations placed on him in the development of angioplasty in Zurich. He intended to take an academic position as Professor in Germany or come to the United States. He said Cleveland, Stanford, and Boston were all interested. I suggested Emory. He had met some of my colleagues the previous year when I brought him to the meeting of the South Atlantic Cardiovascular Society at Kiawah Island, SC. It was a relaxed and informal atmosphere that seemed to make him feel at home.
I invited him to visit Atlanta, Ga, during a trip to Jack Vogel's American College of Cardiology Snowmass (Colo) meeting. He took me up on the invitation, and then I had to spring the news to Dr Willis Hurst, Chief of Medicine. Despite some early reservations, after meeting Andreas, Dr Hurst was completely enthralled and became crucial in the recruitment effort. My colleague John Douglas and I had been struggling with angioplasty, and we were relieved when Andreas finally telegraphed that he was coming to Emory.
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Progress in the 1980s |
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Angioplasty developed at a rapid pace throughout the early 1980s. Many of the early operators were busy trying to define the predictors of complications and restenosis and to train fellows as well as those attending teaching courses.15 16 17 18 19 20 21 22 23 24 25 26 27 Even before Andreas' arrival in the United States, he had been very instrumental in setting up the National Heart, Lung, and Blood Institute registry for angioplasty.28 29 The early investigators in North America joined together in this registry. Industry, supported in large measure at that time by the major supplier of balloon catheters, USCI's David Prigmore, agreed to restrict catheter delivery to those who would cooperate with the NHLBI registry. Early in the 1980s, many investigators began to make important contributions. There is no hope of recounting all the important contributors, but it should be said that Hartzler was pushing the envelope of angioplasty toward more multivessel disease.30 31 Meyer et al were performing angioplasty for acute myocardial infarction,32 and Simpson was building his company (ACS) with an over-the-wire system to provide strong competition for the development of balloon catheters. In 1982, at the request of Andreas and others, steerable guide wires were developed that dramatically improved the ability to reach distal segments of the coronary tree. Catheter development continued with the introduction of very-low-profile balloon materials that would allow high-pressure inflations, which further expanded the horizons of angioplasty.
By 1984, angioplasty had developed enough to test it against bypass surgery. Gruentzig favored such a course and proposed the first randomized trial for our group at Emory. Unfortunately, he would not survive to see this project through. In 1987, we finally received NIH approval of our R01 grant on the Emory Angioplasty versus Surgery Trial, the first to test multivessel PTCA versus coronary artery bypass graft surgery.33 34
Although most new devices had their evolution in the late 1980s, many of these developments were ongoing before Andreas's death. In fact, Andreas experimented with laser therapy in Zurich before coming to America and also worked with other devices to open coronary arteries. One of the most interesting methods was the drilling machine. This consisted of a thin elastic wire, the distal end of which was bent into an elliptical form. With that end in the artery, the proximal end was connected to a rotating drill with a speed of 3000 revolutions per minute. When spinning, the wire developed the form of an ellipse, similar to an eggbeater, and displaced the atherosclerotic material against the arterial wall. The device was tested in animal models in April and July of 1972; however, pressing work with balloon catheters interrupted further development of this method.
Directional atherectomy,35 36 developed by Simpson, was in early development in 1987. Rotary ablation was conceived by Auth and reduced to practice for treating hard and calcified lesions.37 Intracoronary stents,38 39 developed primarily by radiologists for use in large vessels, were being advocated for use in coronary circulation. Gianturco visited and encouraged Andreas to support further research development of his device. Andreas asked Roubin to pursue this approach in animal experiments, and John Douglas and I subsequently placed the first clinical stents in the United States in 1987.
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New Technologies of the 1990s |
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The 1990s have been the decade of application of the methods developed in the 1980s. Directional atherectomy has gone through a period of major enthusiasm, followed by a reduction in its use after the performance of the first industry-supported objective trial of a new technology against balloon angioplasty (the Coronary Angioplasty Versus Excisional Atherectomy Trial).40 Results from the Balloon versus Optimal Atherectomy Trial investigation are eagerly awaited. The rotablator, released gradually through the mid-1990s in the United States, has gained popularity,41 while its use in Europe has begun to wane. A trial of the rotablator technique, Study To determine Rotablator And Transluminal Angioplasty Strategy (STRATAS), is under way. Laser therapy captured the imagination of many,42 but its high cost and need for technological improvements has resulted in little use of this therapy over the past few years. Use of a laser wire to treat total occlusions is being tested currently. Intracoronary stents remain the single most important successor to balloon technology. From a cautious beginning as a bailout device for failed balloon angioplasty, stenting has become a mainstay of interventional cardiology, with over 16 designs in human trials.
Where has interventional cardiology arrived in 1996? Worldwide trials of angioplasty versus surgery, including the Emory Angioplasty Surgery Trial and the Bypass Angioplasty Revascularization Investigation, have been completed and analyzed.43 44 45 46 47 48 49 50 51 The conclusion that angioplasty can be performed in suitably selected, multivessel-disease patients has been established in over 5000 patients randomized in these studies; however, the recurrence rate still drives an excess of angioplasty patients toward repeat procedures. It is often pointed out that most of these trials did not use the new technologies of coronary angioplasty. Technical advances have improved the ability to perform angioplasty with low-profile balloons, long balloons, high-pressure balloon material, perfusion and monorail devices, and improved guide wires and guide catheters. In addition, the new technologies of directional atherectomy, rotary ablation, and stenting have contributed materially to our ability to handle a broader spectrum of lesions. The degree to which these new technologies can improve on the long-term results achieved with angioplasty remains to be proved.
The Remaining Problem of Restenosis
It is obvious from these studies that angioplasty remains a viable
alternative to surgery for suitably selected patients but that its
place cannot be firmly established as the preferred therapy until the
restenosis problem is solved. Despite these technologies,
restenosis remains a significant problem. Many trials have
proved to be negative or inconclusive. Notable among these are trials
of ACE inhibitors,52 serotonin
antagonists,53 somatostatin
analogues,54 ß-hydroxy-ß-methylglutaryl–CoA
reductase inhibitors,55 and 
-3 fatty
acids.56 57 Some trials have shown improvement in clinical
or angiographic findings, such as trials of nitric oxide donors and
possible platelet-derived growth factor
inhibitors.58
Drugs designed to prevent early complications of angioplasty by preventing intra-arterial thrombosis also may affect late restenosis. The EPIC (Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications) trial showed not only a one-third decrease in acute complications but also a sustained decrease in clinical events through 6 months in patients treated with a C7E3 antibody to the platelet glycoprotein IIb/IIIa.59 Other trials of drugs that inhibit platelet aggregation, such as the Randomized Efficacy Study of Tirofiban (MK-383) for Outcomes and Restenosis (RESTORE) trial and the EPILOG (Evaluation in PTCA to Improve Long-term Outcome With ReoPro GBP IIb/IIIa Blockade) trial, are designed to test whether angiographically proved restenosis can be reduced by this method.
The lack of success of systemic drug restenosis trials has often been attributed to the inadequacy of the dosing and the low tissue concentrations achieved. Because of that, a great deal of interest has developed in local drug delivery. Approximately 10 local-delivery catheters have been developed, and some of them have gained Food and Drug Administration approval. Unfortunately, most of these devices are still in search of a use. One of the most promising applications of local drug delivery is to transfer antisense oligonucleotides directly into the vessel wall to signal the cells to stop replicating and therefore block neointimal formation after an intervention. Although this effect can be well demonstrated in cell culture and certain experimental preparations, problems regarding efficiency of local delivery and the dwelling time of the agent remain unresolved. Additional local-delivery methods, such as retained drug-containing polymer, iontophoresis, or electroporation, may be required. It is encouraging that delivery of low-dose ionizing radiation at the time of an intervention may signal programmed cell death (apoptosis) and inhibit or stop the neointimal proliferative response. This effect has been well demonstrated in porcine coronary arteries and is now being applied in the first clinical trials.60 61
Most encouraging of recent trials, however, are those carried out with the Palmaz-Schatz stent. The landmark Stent Restenosis Study62 and Belgian Netherlands Stent Study (BENESTENT)63 have shown a reduction in restenosis rate for the first time with the use of the stent. Improved antithrombotic strategies and development of antithrombotic stent coatings will lead to expanded use of this method. Results from the recently reported BENESTENT II pilot study, which used a heparin-coated stent, are most encouraging.64
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The Future |
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As we enter the second half of the 1990s, clinical interventional cardiology is influencing molecular biology. Scientists with diverse backgrounds are focusing on the problem of coronary artery disease, particularly the healing process after angioplasty. The failings of various systemic therapies have led to heightened enthusiasm regarding the control of cell growth and vascular contraction of the vessel wall by delivery of high-concentration compounds in the local environment. Potent antithrombotic strategies, genetic engineering, and radiation biology are all coming to the fore in an effort to control this stubborn problem. Interventional cardiology provides a fascinating natural laboratory in which to study arterial disease. It is undeniable that the development of interventional cardiology has spurred on a heightened understanding of coronary atherosclerosis and has enabled significant resources to be focused on this problem. As we approach the 21st century, the impact of molecular biology on interventional cardiology will be felt increasingly.
With the successes of angioplasty come responsibilities. In an effort to educate all who are interested, we have created an oversupply of interventional cardiologists in the United States. Perhaps if interventional cardiology had remained a balloon technology for the treatment of single discrete lesions, it would remain a logical technique for application by all who perform cardiac catheterization. However, interventional cardiology has become more complex and requires knowledge of the use of many devices, interpretation of intravascular ultrasound, the healing response of arteries, pharmacological interventions that can be helpful, research directions aimed at the prevention of restenosis, and treatment of acute syndromes. It will be critical that experienced interventional cardiologists be available as consultants in the future healthcare system. It is unlikely that 5 to 10 years from now interventional cardiology will remain a sideline for cardiologists, but rather it is likely to evolve into its own subspecialty of cardiology, as has electrophysiology. This change will not be accomplished without discomfort and will not be universally applicable owing to local situations, but because of the explosion of knowledge in the field, these changes will evolve.
This explosion of knowledge would not have surprised Andreas Gruentzig. He was ahead of us in the early development of angioplasty, and I am sure he would have remained so had he lived. How this discipline will evolve in the future one can only guess. Will the insights into basic molecular mechanisms gained during the era of interventional cardiology bring us closer to the ultimate goal of eliminating coronary artery disease as a major health risk? If so, no one would be more pleased than the man who launched this fantastic voyage, Andreas Gruentzig.
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