American College of Cardiology 48th Annual Scientific Session March 7-10, 1999 Myocardial Revascularization by Angiogenesis There is a growing number of CAD (coronary artery disease) patients with severe angina, despite the best available treatments. This article discusses new ways to improve the heart's blood flow using approaches like PMLR (percutaneous myocardial laser revascularization) and angiogenic growth factors. Angiogenesis and Vasculogenesis Angiogenesis means causing new capillaries (tiny blood vessels) to form so that blood flow is improved in an area that had restricted blood flow before. Vasculogenesis is the enlarging of already existing blood vessels, along with creation of new ones. Direct Laser Revascularization Pathologic changes found within one week of laser revascularization show open channels bordered by dead heart tissue. The channels may be filled with a platelet-heavy blood clot. After one month, these channels have closed with a vascular scar. New tiny blood vessels are formed within the scar, and sometimes these blood vessels enlarge. The capillary density in these scars is actually higher than in normal heart tissue. Researchers are studying whether holes made in the myocardium using a laser are comparable to those made mechanically or with radiofrequency energy - in terms of their angiogenic and vasculogenic effects. Early data suggest that new capillaries and collateral vessels result from all of these methods. It also seems that even a very shallow channel (just piercing the endocardium) made during PMLR leads to excellent angiogenesis. These channels aid the blood vessel rich myocardial network. Making shallower channels may result in a safer and simpler procedure. BIOSENSE Technology With PMLR, precise mapping of the myocardium to accurately guide the laser is important. The BIOSENSE system is an inside-the-body navigation system which maps electromagnetic currents emitted from a catheter. An advanced computer workstation displays a 3D view of the left ventricle. This technology is safe and accurate. It is currently used in mapping and ablation of arrhythmias (RFA). Trials are now evaluating the use of the BIOSENSE system in assisting PMLR and growth factor therapy. An 8F catheter has been designed which does both BIOSENSE mapping and laser revascularization. Another catheter is being developed which performs both BIOSENSE mapping and needle injection into the heart wall, allowing growth factors or gene therapy to be used during the cath procedure. Angiogenic Growth Factors Animal and human trials are testing angiogenic growth factors for ischemic heart disease. While many growth factors have been identified, most research has been on vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Dr. Michael Simons from Beth Israel Hospital in Boston summarized the results of 2 human phase one FGF trials. Phase I Local FGF During CABG Twenty-four patients were in a trial comparing placebo to local delivery of FGF during bypass surgery. Patients were in 1 of 3 groups: placebo low-dose FGF (10mcg) high-dose FGF (100mcg) FGF was given using microcapsules sewn into the epicardial surface during surgery. After a 16 month followup, there seemed to be improved blood flow of the heart in patients from the high-dose FGF group, compared to placebo. There was no difference between the placebo and low-dose FGF groups. Because this phase one trial showed that local FGF delivery was safe, a phase 2 trial comparing high-dose FGF with placebo is now underway. Phase I Intracoronary and Intravenous FGF Results from a phase one study of intracoronary (IC) and intravenous (IV) recombinant FGF also look promising. This study enrolled 66 patients with severe CAD. Fifty-two patients received IC FGF and 14 received IV FGF. Patients increased their treadmill exercise times by an average of 105 seconds at the 60-day treadmill test. Quality of life tested with the Seattle Angina Questionnaire showed 20% improvement. Conclusions From Growth Factor Trials Results of phase one FGF trials look good. A phase 2 trial of IC FGF is underway, with a projected enrollment of 300 patients. The phase one VEGF trials also look good. However, the phase 2 VEGF trial (VIVA) showed that while VEGF was safe, it did not improve exercise time or angina scores. Gene Therapy Many trials are evaluating gene transfer therapy in patients with severe ischemic heart disease. Various delivery methods are being studied, including IC, direct injection into the heart, and intrapericardial. The theory is that gene transfer may reduce restenosis and improve the heart's blood flow. Dr. Yla-Herttuala fromt the Kuopio University Hospital in Finland described the results of a phase one study testing catheter based gene transfer in humans after angioplasty. Ten patients received VEGF and 5 got placebo after angioplasty. A catheter was used for the 10-minute IC treatment. All patients were followed up at 6 months. No significant differences were seen between the 2 groups. This phase one trial showed gene transfer after angioplasty to be safe but more studies are now underway to see if it really works. Growth Factors: Unanswered Questions It is unclear which growth factor is best. The best delivery method also remains unclear. Whether delivering growth factor protein or gene therapy is best is currently unknown.