Keith A. Horvath, MD and David A. Fullerton, MD
Department of Surgery
Division of Cardiothoracic Surgery
Northwestern University Medical School
Feinberg Cardiovascular Research Institute
Chicago, Illinois

Despite the success of conventional methods of revascularization for end-stage coronary artery disease, such as coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angiography (PTCA) with stenting, there remain a growing number of patients whose disease is not amenable to conventional revascularization. This may be confined to one vascular territory of their heart or may be global. It is for these patients that several novel treatments have been devised.

Transmyocardial laser revascularization (TMR) has been performed on over 6,000 patients worldwide since 1990. Early animal work that we performed demonstrated the functional recovery and viability of ischemic myocardium treated with TMR. This research was originally used in an ovine model, in which few collaterals form, and all perfusion to the ischemic heart was via the TMR channels. Since then, we have employed a large animal model of chronic myocardial ischemia that mimics the clinical scenario. For this preparation, an ameroid constrictor is placed around the left circumflex artery of a pig. The metal encased constrictor contains a hydrophilic substance that over the ensuing weeks totally occludes the artery. The resulting constriction increases the collateral development in the myocardium subtended by the ameroid. Collateral vessels in the pig consist of a fine network of endomural vessels similar to the coronary collateral vessels present in humans. Once the occlusion has been set, the animals undergo a second operation during which baseline evaluation of the ischemic myocardium compared to the normal myocardium is obtained. The ischemic zone is then treated. This treatment has taken on a variety of forms using different devices and agents. In addition to various wavelengths of laser light, we have used thermoelectric needles, ultrasonic needles, fibers, and angiogenic growth factors in the form of proteins and viral vectors.

Initially, we evaluated the mechanisms whereby TMR achieves its clinical benefit. The results in patients indicate a significant decrease in symptoms, with 70% of the patients dropping at least two angina classes and 30% of them having no angina post-TMR. Of the various mechanisms entertained, including channel patency, denervation, placebo, and angiogenesis, our work has demonstrated the importance of angiogenesis. We have shown that laser TMR results in an upregulation of the messenger RNA for angiogenesis such as VEGF. The ensuing angiogenic response has lead to increased perfusion of the ischemic myocardium. Most importantly, there has been a significant recovery of myocardial function in the ischemic zone treated by TMR. These results have been confirmed by a Northern Blot analysis, RT-PCR, dobutamine stress echocardiography, microspheres, as well as perfusion and cine MRI.

While other mechanical devices have induced angiogenesis, it appears that the delivery of laser energy to ischemic tissue leads to a more meaningful angiogenesis than is what is typically seen as part of the healing process. We are carrying this work to the next phase, which involves the addition of gene therapy to further stimulate the angiogenic response. Clinically, we have experienced the ability to provide a more complete revascularization by bypassing arteries in patients that can be bypassed and lasering areas of the heart that can not be grafted. We foresee the addition of gene therapy with TMR to further improve these results.

While it is clear we have a reasonable understanding of the macrocirculation of the heart, this work highlights the relative lack of knowledge of the microcirculation and as patients exhaust the conventional methods of revascularization, this new knowledge will become increasingly important. In addition to this work, our division is also involved with the following projects:

David A. Fullerton, M.D.:
Cytokine and TNF signaling and production in human myocardium during cardiopulmonary bypass.

Arthur S. Palmer, M.D:
Correlation between the impairment of cardiac lymphatics and coronary artery disease.

James W. Frederiksen, M.D.:
Alternative anticoagulation for the conductance of cardiopulmonary bypass.