Coronary artery disease is the most prevalent cardiovascular condition requiring the care of the cardiologist. Although significant advances have been made in the medical management of these patients, many require coronary revascularization for relief of symptoms or manifestations of ischemia or for prolongation of life. This session reviewed history of pharmacologic and operative revascularization approaches and speculated on what therapies might be available for the next century.Coronary Revascularization: Current Status and Future Needs
James T. Willerson, MD,[1] Houston, Texas
Dr. James T. Willerson provided an overview of the advances in revascularization techniques. One of the initial approaches was to create a bypass using a segment of carotid artery between the descending aorta and the left coronary artery. Development of the heart-lung bypass machine allowed surgery to be performed on a non-beating heart. The first bypass of the left anterior descending artery with a saphenous vein was performed in 1964. At present, coronary bypass has become a highly refined operation with well-documented effectiveness in relieving ischemia and prolonging life in selected patient subsets.One limitation of coronary bypass is that saphenous vein grafts degenerate over time and experience progressive lumenal narrowing and eventual occlusion. Modification of the cellular structure of venous grafts by genetic engineering, however, appears promising as a method to enhance durability (cf. "State of the Art Gene Therapy," Monday).
Dr. Willerson emphasized the importance of initiating current and future pharmacologic therapies to attenuate the progression of atherosclerosis. Another problem requiring attention is restenosis following balloon angioplasty or stenting. Intracoronary radiation, local gene therapy, and systemic inhibitors of thrombosis are likely to be effective in addressing this issue.
Therapeutic Angiogenesis
Stephen E. Epstein, MD,[2] Washington, DC
The development of intracoronary collateral vessels can provide an important accessory source of myocardial blood flow to patients with coronary artery disease. For unknown reasons, however, not all patients demonstrate collaterals even in the presence of very severe coronary obstruction. Accordingly, intensive investigation is now focused on methods that would have the potential to stimulate the development of collaterals in humans.Several proteins have been identified that participate in the growth of new blood vessels. Some of these include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and angiopoietin. Experimental studies in dogs with ameroid constrictors placed on their left anterior descending coronary arteries have demonstrated the ability of these factors to enhance regional blood flow via collateral vessels. A small study in patients undergoing coronary artery bypass indicates that FGF, injected into myocardium at the time of surgery, can stimulate small vessel formation, demonstrable by angiography. The single randomized, placebo-controlled clinical trial evaluating intracoronary and intravenous VEGF, however, did not show any clinical benefit for treated patients.
Administering single growth factors may not be an appropriate approach to obtain optimal results. The actions of these agents are extremely complex and not fully understood. A single agent may stimulate some processes favoring angiogenesis while also triggering some that may oppose this effect.
Dr. Epstein emphasized the importance of distinguishing angiogenesis from arteriogenesis. Angiogenesis is the sprouting of endothelial cells from an existing artery, whereas arteriogenesis is the expanding and remodeling of an existing artery. Arteriogenesis may be the actual desired outcome. There is also a need to identify and characterize those factors that trigger arteriogenesis. In humans, a decrease in downstream (distal) intra-arterial pressure creates an increase in shear stress that may be a stimulant for arteriogenesis. This may occur because an increase in shear stress attracts monocytes to the blood vessel wall. These moncytes can then enter the wall and trigger a cascade that results in the local synthesis of angiogenic factors.
Finally, studies of angiogenic factors must consider 2 potential untoward effects. If cell proliferation occurs at the wrong site within a coronary, for instance at an atherosclerotic plaque, plaque growth might be observed. Also, there is a report of a tumor-like hemangioma resulting from administration of an angiogenic factor in an animal preparation.
Clearly, angiogenesis is an extremely important area for continued investigation. Although this approach may eventually translate into a practical, safe, and effective therapy for patients with coronary disease, considerable time and effort will be required before that goal can be achieved.
Acute MI: Reperfusion Pharmacotherapy
Elliot M. Antman, MD,[3] Boston, Massachusetts
The precipitating cause of an acute myocardial infarction (AMI) is an abrupt coronary artery occlusion. A significant component of this obstruction is thrombus that arises from a split or fissuring of an atherosclerotic plaque. The primary goal of treatment of this disorder is to restore normal antegrade flow, quickly and safely. The pharmacologic approach involves the combined use of a fibrinolytic agent, an antithrombin, and an antiplatelet agent.Tissue-type plasminogen activator (t-PA), administered in an accelerated dosage regimen, is considered the current standard of care for patients treated with thrombolytic therapy. New formulations, derived from the t-PA molecule, enable single bolus administration without compromising effectiveness. The ability of these thrombolytic agents to achieve normal, TIMI (Thrombolysis In Myocardial Infarction) grade 3 flow is not observed in all AMI patients. Strategies combining t-PA with other agents that influence thrombosis by means of a different but complementary mechanism have been investigated. The TIMI 14 trial compared an accelerated regimen of intravenous t-PA 100 mg versus t-PA 50 mg combined with intravenous administration of the glycoprotein (GP) IIb/IIIa inhibitor abciximab. Preliminary results of this trial suggest that the addition of abciximab increases the proportion of patients who achieve normal perfusion during AMI.
Other investigations have focused on administration of antithrombins, with unfractionated heparin being the prototype. Recent data suggest that a low-molecular-weight heparin, such as enoxaparin, appears superior to unfractionated heparin in the treatment of patients with unstable angina and non-Q-wave MI. Further studies of low-molecular-weight heparins in conjunction with thrombolytics are pending.
In the final analysis, it is likely that AMI patients in the 21st century who receive pharmacologic reperfusion therapy will receive a thrombolytic, an intravenous antiplatelet agent, and possibly an antithrombin other than unfractionated heparin.
Catheter-Based Revascularization: Beyond the Stent
David O. Williams, MD,[4] Providence, Rhode Island
Catheter-based coronary intervention can be characterized as an area of continuous development and refinement. These developments have been directed at improving the safety and effectiveness of percutaneous coronary interventions (PCI) and increasing the applicability of PCI.Stents have had a major impact in improving the safety and effectiveness of PCI. The Dynamic Registry enrolled sequential waves of patients having coronary interventions at 15 sites in the United States, Canada, and Europe. The first wave was initiated in 1997-1998. The second wave began in February 1999 and was completed in 2 months. A comparison of device use in this database indicates that during this time, stent usage increased from 60% to >70%. Furthermore, with the increase in stent usage, certain complications, such as abrupt closure, have declined substantially. The durability of PCI has also been enhanced. In comparison to a registry of balloon angioplasty alone, recent results demonstrate a 40% reduction in the need for repeat PCI or coronary bypass over the span of a 1-year follow-up.
Certain problems remain, however, that have not been solved by stents. For selected patients, safety is still a concern. Patients with lesions in aorto-coronary vein grafts experience embolization caused by plaque debris that results in slow coronary flow, ischemia, and, at times, a large infarction. New devices can now extract thrombus that complicates these lesions, and small temporary filters can be placed in the distal graft to capture emboli.
Stents have increased the durability of PCI but have not eliminated restenosis. Not all patients receive stents, and of those who do, some develop restenosis within the stent. Conventional techniques have been only partially successful in relieving and preventing in-stent restenosis. Irradiation, known to be effective in treating other proliferative disorders, has been investigated for the treatment of in-stent restenosis. Results of observational and randomized trials using irradiated stents have consistently shown a substantial benefit of irradiation over standard PCI techniques. Early trials also indicate that radiation may reduce the risk for restenosis in patients treated by balloon angioplasty without a stent. We look forward to formal approval of radiation systems for the routine treatment of patients.
A third goal for catheter-based revascularization techniques is to provide therapy to patients who are currently unable to be treated by either surgical or other available methods. Typically these are patients with diffuse coronary disease, in whom coronary disease has been long-standing and surgical bypass has already been attempted. The endomyocardial laser, a stimulant of local angiogenesis, appears to be one possible therapeutic option. Several randomized but unblinded clinical trials have consistently demonstrated improvement in clinical status and indices of ischemia. These trials are limited, however, in that for obvious reasons, patients and providers were not blinded as to therapy, ie, active laser treatment or placebo. We and others are currently participating in a double-blinded trial wherein laser therapy is guided by a computer-generated map. The results of this trial, the DIRECT (DMR In Regeneration of Endomyocardial Channels) Trial, should answer the question with assurance.
In addition, catheter techniques are being developed to allow local intramyocardial injection of pharmacologic agents. This approach may be the best for the further evaluation of angiogenic factors.
Finally, catheter-based techniques are being developed to allow the anterior intraventricular vein to serve as a bypass conduit for lesions located in the left anterior descending artery. A small fistula can be created proximal and distal to the obstruction. Occlusion of the proximal and distal segments of the vein thus isolates the segment and serves as the bypass. For patients with diffuse LAD disease, a proximal fistula with the vein coupled with more proximal occlusion of the vein allows the vein to serve as the arterial channel to anterior wall myocardium.
Innovative Approaches to Coronary Bypass Grafting
James A. Magovern, MD,[5] Pittsburgh, Pennsylvania
Several new approaches have been developed to refine further the well-established coronary bypass operation. One, the MIDCAB (Minimally Invasive Direct Coronary Artery Bypass), involves a small thoracotomy and does not require use of the heart-lung machine. The procedure is designed for isolated internal mammary-LAD anastamoses. Most surgeons have not adopted this procedure, however, as it is technically difficult and limited to patients with single-vessel LAD disease.Hybrid procedures combining PCI and surgery have also been performed. In this instance, a patient would have a MIDCAB performed for an LAD lesion and then have a stent placed by the interventional cardiologist for a lesion in some other artery. Because of special equipment and resource needs, this hybrid procedure has been performed very infrequently.
Using the port-access approach allows bypass to be performed without a sternotomy. The patient is, however, placed on cardiopulmonary bypass by means of special catheters. This is a time-consuming and expensive technique that has not been embraced by the surgical community.
A final approach discussed by Dr. Magovern was the OPCAB (Off-Pump Coronary Artery Bypass). This technique involves a sternotomy, but the patient is not placed on cardiopulmonary bypass. The surgeon operates on a beating heart. Avoidance of cardiopulmonary bypass is considered to be an important advantage. This procedure has been accepted by surgeons and is becoming more popular (cf. Risk Stratification and Early Intervention in Congestive Heart Failure by Robert C. Bourge, MD).
Important advances in coronary revascularization have been achieved during the last decade of the 20th century. Major new achievements are realistic expectations for the first decade of the 21st century.
References
- Willerson JT. Coronary revascularization: current status and future needs. Presented at the American Heart Association 72nd Scientific Sessions, Atlanta, Ga, November 7-10, 1999. Plenary Session I: Revascularization in the 21st Century, Nov 7.
- Epstein SE. Therapeutic angiogenesis. Presented at the American Heart Association 72nd Scientific Sessions, Atlanta, Ga, November 7-10, 1999. Plenary Session I: Revascularization in the 21st Century, Nov 7.
- Antman EM. Acute MI: reperfusion pharmacotherapy. Presented at the American Heart Association 72nd Scientific Sessions, Atlanta, Ga, November 7-10, 1999. Plenary Session I: Revascularization in the 21st Century, Nov 7.
- Williams DO. Catheter-based revascularization: beyond the stent. Presented at the American Heart Association 72nd Scientific Sessions, Atlanta, Ga, November 7-10, 1999. Plenary Session I: Revascularization in the 21st Century, Nov 7.
- Magovern JA. Innovative approaches to coronary bypass grafting. Presented at the American Heart Association 72nd Scientific Sessions, Atlanta, Ga, November 7-10, 1999. Plenary Session I: Revascularization in the 21st Century, Nov 7.
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