Abstract
Introduction
It has been proven that blood supply to the heart can include blood from noncoronary collateral circulation. Whether this network can somehow be augmented to provide an alternative therapy for ischemic patients is an intriguing hypothesis with no clear answer yet due to the challenging nature of this research field. In an attempt to enhance noncoronary collateral blood flow, we experimented with left internal thoracic artery ligature and angiogenic growth factors in a canine model.
Materials and methods
Eight dogs weighing between 20 and 29 kg were scheduled for three operations each. Neutron-activated microspheres were used for blood flow measurement throughout the study. The first operation was a left thoracotomy for ameroid constrictor positioning at the proximal segment of the circumflex coronary artery. Three weeks later the left internal thoracic artery was ligatured distally. A micro-pump was positioned in the mediastinum, connected with a small catheter inserted in the proximal segment of the left internal thoracic artery for slow delivery of vascular endothelial growth factor. The protocol called for a coronary angiography 4 weeks later, sacrifice of the animals, and explantation of the heart for microsphere analysis.
Results
Four of the dogs failed to tolerate ameroid constrictor positioning by thoracotomy and died after the first operation. The remaining four dogs underwent a second operation to ligate their left internal thoracic arteries and implant micro-pumps with catheters. The implant was a success, but only one dog survived in the postoperative period. When the last dog was voluntarily sacrificed after a third operation, coronary angiography showed no neovascularization, nor did heart slice analysis reveal microspheres.
Conclusions
Despite the technical challenge of building research protocols to exactly quantify blood from noncoronary arteries, there are many historical, anatomical, physiopathological, clinical, radiological, and surgical indications suggesting that blood flow from extracardiac structures may play an important role in ischemic heart disease. Our preliminary investigation combining internal thoracic artery occlusion and angiogenic growth factors was unsuccessful for several reasons, the main one being it was too heavy a protocol for the dogs. Despite this, we think that noncoronary collateral blood flow represents an intriguing research field worthy of debate and further study.
1
Introduction
Several myocardial blood supply strategies have been investigated in recent years, including cell-based therapy, protein-based angiogenesis, gene therapy using an adenoviral vector, and myocardial laser revascularization . So far, none of these approaches has led to a novel, routine practice for the treatment of ischemic heart disease, still one of the main causes of morbidity and mortality in Western countries . Noncoronary collateral blood flow (NCCBF) or noncoronary collateral circulation (NCCC) is a virtually ignored topic, with very few publications in existence. Based on four aspects as follows, our hypothesis is that enhancement of NCCBF may represent an alternative myocardial blood supply strategy and that combining internal thoracic artery occlusion with angiogenic growth factors may represent a way to achieve this objective . Firstly, there is evidence that ischemic stimulus may cause the internal thoracic arteries (ITAs) to develop major collateral branches, as demonstrated in cases of chronic occlusion of the abdominal aorta, when the ITAs represent, in some instances, the sole source of blood supply for the lower limbs . Connections have also been demonstrated between ITAs and native coronary arteries, both in living patients and by postmortem angiography (12% of cadavers) . This suggests that ATIs have high plastic potential and that this may be solicited in hypoxic conditions. We expect that, in cases of myocardial ischemic stimulus, collateral blood flow from the ITAs is diverted first to the heart rather than to the chest wall. Secondly, during aortic valve surgery, arterial blood can be seen to flow out from the coronary ostia, while during coronary surgery blood may flow out from the incised coronary artery, despite adequate venting and correct aortic cross-clamping. It is not even rare for patients to show an ejection fraction equal to or greater than 55%, despite occlusion of the right coronary artery and sub-occlusion of the left main artery. These phenomena suggest the existence of alternative ways for blood to reach the heart, for no other easy explanation exists. We postulate that the answer lies in the network constituted by the NCCBF. This network arises from mediastinal, esophageal, bronchial, and intercostal arteries. Blood reaches the myocardium through small channels connected with aortic and pulmonary artery vasa vasorum, and with channels located within the pericardial reflections surrounding the pulmonary and systemic veins . Previous studies suggested that over one-fifth of patients have connections between the atrial branches of the coronary and bronchial arteries, with bidirectional flow depending on the clinical circumstances . Bronchial-to-coronary artery flow is possible when bronchial arterial pressure is increased, as with severe chronic obstructive coronary disease ; coronary-to-bronchial artery flow is possible when coronary artery pressure is increased, as with supravalvular aortic stenosis . Intuitively, a gradient may cause reverse flow to the coronary arteries if the pressure regimen within the coronary arteries is reduced by significant atherosclerotic disease. Thirdly, the fact that the ITAs are a source of NCCBF was demonstrated by Hudson et al. , Battezzati et al. , Moberg , Glover et al. , and Bloor and Liebow . We also recently detected in a patient, using contrast-enhanced computed tomography (CT), a direct connection from the LITA to the left anterior descending artery ( Fig. 1 A and B), developed following a pulmonary infection. Collaterals leading to the heart arise especially from the pericardiophrenic branches. In the rat, such connections play a big role, offering double circulation to the conduction system . Fieschi first performed the bilateral ligation of the internal thoracic arteries in a single patient in 1939. The patient recovered and was still free of angina 1 year later . Battezzati et al. , in 1954, demonstrated the existence of direct connections between the ITAs and the myocardium and epicardium by injecting methylene blue into the arteries and observing the onset of blue areas on the surface of the heart and within the myocardial muscle. In man, they repeated the same operation as that of Fieschi : a small bilateral incision between the second and third rib was performed to approach the ITAs under local anesthesia. The goal was creating a local hypertensive status to increase the perfusion pressure within the channels leading to the heart. Results were very promising because in most patients both angina and electrocardiographic signs of ischemia disappeared. In the United States, Glover et al. repeated the experiments with canine models as well as the clinical application in man of ITA ligation with similar encouraging results. Lastly, a role was attributed in our experiment to vascular endothelial growth factor (VEGF). This is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation and migration, and new vessel formation. It is a direct growth factor because it may exert its activity both in vitro and in vivo . In an attempt to enhance noncoronary collateral blood flow, we established an ischemic canine model for the first experiment and we experimented with left internal thoracic artery ligature and angiogenic growth factors.
