Stimulation of coronary collateral growth: Current developments in angiogenesis and future clinical applications Richard W. Kass, DO, Morris Philadelphia, Pa.

N. Kotler,

MD, and Shahriar

“The great potential of collateral development lies in its promise to alter the natural history of coronary artery disease.” W. Schaper

Over recent years evidence has accumulated favoring a significant functional role of coronary collateral vessels in humans with coronary artery disease.iegAs a result, efforts to identify factors involved in initiating and controlling the growth of these vessels have intensified. An understanding of these evolving mechanisms has opened up some exciting new areas of research with far-reaching potential applications in clinical cardiology. TRANSFORMATION, RECRUITMENT

ANGIOGENESIS,

AND

In the normal human heart, a network of tiny vascular channels exists within the myocardium, ranging in size from 20 to 200 pm in diameter. These channels interconnect with one another (primarily in subendocardial regions) aswell as with the major epicardial coronary arteries and their branches.iO Imbalance of myocardial oxygen supply and demand over time may induce changes in some of these collateral channels, resulting in gradual dilatation and transforma-

From Albert

the Division of Cardiovascular Disease, Department Einstein Medical Center, Temple University School

This study was supported in part Research, Philadelphia, Pa. Received

for publication

Reprint requests: Morris Einstein Medical Center, Philadelphia, PA 19141. 411133930

466

June

by the Women’s

10, 1991;

N. Kotler, Third Floor,

accepted

MD, Division Klein Bldg.,

of Medicine, of Medicine.

League Aug.

for Medical

1, 1991.

of Cardiology, York and Tahor

Albert Roads,

Yazdanfar,

MD.

tion into larger vessels with greater blood-carrying capacity. The process of transformation has been studied extensively in animal models. In a series of experiments, Shape@ used a plastic ameroid constrictor ring to induce gradual coronary occlusion in dogs, resulting in significant development of functional collateral circulation. Initially, a microvascular “response to injury” phase was observed during the first 2 weeks following occlusion,12 with passive dilatation of the existing channels and damage to the vessel walls. Perivascular inflammation ensues, with rupture of the elastic lamina followed by extravasation of plasma proteins, platelets, and white blood cells. Monocytes also migrate into the vascular wall and appear to play a significant role in the transformation process, perhaps by production of mitogenic factors enhancing smooth muscle cell growth.12 Over the next few months a vascular growth phase takes place, characterized by increased mitotic division of endothelial cells, smooth muscle cells, and fibroblasts. Further cell proliferation with deposition of collagen and elastin gradually results in the development of mature remodeled vessels that resemble normal coronary arteries of similar size. Approximately 90 5%of their maximal capacity is attained by 4 weeks following occlusion, with collateral resistance dropping rapidly over the first 4 weeks and then leveling off over the following months.13 In addition to collateral transformation, new vessel growth or angiogenesis appears to take place, resulting in the formation of new capillaries where no prior vascular channels existed. A summary of in vivo and in vitro studies that have helped elucidate events involved in this process has recently been published by D’Amore and Thompson14 (Fig. 1). Initially, endothelial cells demonstrate an increase in number of organelles, surface projections, and activity of

Volume

123

Number

2

Coronary collateral

growth

487

1. Schematicrepresentation of the formation of a new blood vessel.Seetext for details. (Reproduced with permissionfrom D’Amore PA, Thompson RW. Annu Rev Physiol 1987;49:453-64.)

Fig.

proteases. These cells then migrate into the interstitial space, with concomitant proliferation of the more proximal endothelial cells along the path of migration. This proliferation may in part be caused by a loss of contact inhibition resulting from the disruption of normal interactions between cell membranes. New lumen formation may then take place as a coalescence of intracellular vacuoles in neighboring cells.15 Pericytes then migrate along the new sprout and arrange themselves around the endothelial cells. Basement membrane structures are subsequently derived from these two cell types. Once transformation or angiogenesis has occurred, the maturing collateral vessels become available for recruitment as the balance between oxygen supply and demand changes and hemodynamic pressure gradients develop across the collateral bed. Recruitment has been studied in animal models and in humans. In humans, collateral vessels seem to become available to accommodate significant blood flow in the event of an acute occlusion only when there has been enough time before the occlusion for adequate maturation to occur.8, X-i9

STIMULATION OF COLLATERAL GROWTH Initiating factors. A number of clinical situations

have been identified as direct or indirect stimuli for the growth of collaterals. Ischemia, however, appears to be the specific common stimulus required for all initiating mechanisms. As noted previously, gradual coronary occlusion has been shown to effectively induce growth and development (for example, the Ameroid constrictor model). Intermittent obstruction has also been noted to enhance collateral growth, as demonstrated in the dog model by improvement of flow and contractile function over time with repeated occlusions.20 Fixed coronary stenosis will usually stimulate collateral growth with luminal narrowing of more than 80 % to 90 % , although collaterals may develop with lesions of lesser severity. Total occlusion may also act as an initiating event. Of these events, gradual and intermittent occlusion appears to be the most effective in generating collateral growth.21 The frequency and duration of the ischemic stimuli are critical, and must be sufficient to initiate cellular and biochemical changes that will ultimately result in collateral development.5> 22

Fetmary 1992 488

Kass, Kotler,

and Yazdanfar

Chronic hypoxia has also been noted to be associated with the development of collaterals. An early autopsy study by Zoll et a1.23 showed a 73% prevalence of collaterals (>40 pm in diameter) in specimens from patients with chronic obstructive pulmonary disease and car pulmonale, as opposed to a 9% prevalence in a normal population23-25 and an 80 % to 99% prevalence in patients with coronary disease.23. 25,26 Dogs subjected to long-term hypoxia over a period of 1 to 3 years have also been shown to have more extensive collateral development.27 Chronic anemia has been implicated as a stimulus for collateral development as well. Studies of South African Bantu tribesmen (who have a high incidence of megaloblastic and iron deficiency anemia in childhood) have demonstrated a high (75 % ) prevalence of collaterals in autopsy specimens.28p 2g Classic experiments by Eckstein30 revealed an increase in retrograde coronary blood flow (i.e., collateral flow) in dogs subjected to long-term anemia. Following transfusion, this collateral flow was no longer demonstrable. Scheel et a1.31 provided evidence of this effect as well in further dog experiments. The hypothesis that exercise may induce collateral growth and development has been extensively investigated. It has often been assumed that since ischemia promotes collateral growth, provocation of ischemia with exercise should enhance collateral growth as well. Although anecdotal and inferential evidence exists to support this assumption,32-36 experimental supportive evidence is not extensive. Eckstein’s early work with dogs37 did demonstrate an increase in retrograde coronary blood flow (a measure of collateral flow) in stenosed vessels among dogs that had been exercised repeatedly. Neil1 et a1.38 found an increase in visualized collaterals with exercise, but no significant increase in measured flow. One study3g did show an increase in retrograde blood flow among beagles that had undergone low level endurance exercise. Evidence refuting an effect of exercise on collateral development is more plentiful. In the Ameroid constrictor dog model, Schaper40 found no significant improvement in collateral flow with endurance exercise. In humans, angiographic studies have shown little benefit from exercise. In an early angiographic study by Helfant et al., 26 there was no correlation between patients who exercised regularly and the appearance of angiographically demonstrable collaterals. This was also substantiated in patients with totally occluded arteries. 41 Prospective studies have also failed to demonstrate a significant increase in

American

Heart

Journal

angiographic collaterals despite exercise programs lasting from 7 months to 3 years following infarction or a baseline angiogram in patients with matched severity of coronary disease.32, 42-44 New collaterals noted among some patients in these studies appeared to be associated with progression of their coronary disease. Judging by the current available evidence, regular physical exercise does not appear to enhance collateral development. It should be noted, however, that most of the human studies have been based on angiographic data. Angiographic data have been of limited value in the assessment and comparison of collateral flow because of methodologic limitations of angiography (including failure to visualize small subendocardial collateral vessels) and variability among groups being compared. More importantly, the degree of ischemia provoked by exercise has not been measured or matched in these studies. Specifically, the frequency and duration of ischemic episodes (critical determinants of collateral growth) must be matched to show any real effect of exercise on collateral growth. It is not surprising then, that exercise studies have shown little if any benefit. Some antianginal agents have also been suggested to possess properties that may stimulate collateral growth. Nitrates in particular have been implicated as having this potential, considering their common use and higher dosages among patients with well-developed collaterals. However, specific evidence of a direct collateral growth-enhancing effect of nitrates is lacking.45 The noted association is most likely a result of the fact that patients taking more frequent and higher doses of nitrates are also more likely to be subjected to more frequent ischemic episodes. Effects of other antianginal medications on collateral growth are likewise probably related to this population selection bias. Mechanical forces. Formation of collateral vessels was originally believed to be mediated by passive stretching of existing channels as a result of pressure changes in the feeder and recipient systems.iOs 11*46,47 Elaboration of more specific mechanical factors felt to promote collateral growth followed. These included development of an intravascular pressure gradient along existing channels with progressive coronary stenosis,48 an increase in tangential wall stress with vasodilatation,4g and increases in viscous drag and shear stress with increased blood flow velocity.“l All of these were noted to occur in parallel with collateral development, but with no specific evidence of a causative role.

Volume Number

123 2

A critical shift in the understanding of factors involved in mediation of collateral growth came about with a key experiment by Pasyk and Schaper.50 They used radioactively labeled thymidine as a marker of DNA synthesis at various stages of collateral development in dog hearts following gradual coronary occlusion with the Ameroid constrictor. Aside from demonstrating increased labeling in arterioles following total occlusion, they observed a small but significant amount of uptake in nearby veins and venules. Since venous channels are not subjected to the same physical forces as arterioles, this suggested that physical forces must play a lesser role in the development of collaterals. It has subsequently been postulated that mechanical forces may be more involved in modeling of collaterals than in stimulation of growth.12 The exact role of these forces is not clear, however. Folkman and Mosconai5 and others51, 52 have shown that endothelial cell shape has an effect on the rate of DNA synthesis, with flatter cells synthesizing more DNA than rounder cells. This implies that changes in endothelial cell shape (as a result of vasodilatation, increases in intravascular pressure, or increased shear stress) may indeed affect endothelial cell growth rates. Biochemical mechanisms. Biochemical mediators have been subjected to an increasing focus in the search for the mechanisms involved in collateral growth and development. Ischemia or hypoxia appear to initiate a sequence of biochemically mediated events resulting in DNA synthesis and mitosis in proliferating endothelial cells, smooth muscle cells, and fibroblasts. This is evidenced by the apparent growth of collaterals toward partially ischemic zones and in all directions in zones distal to a totally occluded artery, implying the presence of a diffusible signal present in ischemic zones.3gl 53 Mediators of inflammation, chemotactic agents, and mitogenic growth factors have all been implicated as participants in the cascade of events occurring in response to ischemia. Cell-to-cell interactions and specialized functions of the extracellular matrix also play a role (Table I). The complex interactions that take place, resulting in neovascular development, appear to be under careful genetic control. Rote of cellular elements. Contact inhibition between endothelial cells is lost in the process of collateral development, allowing proliferation to occur.12 This is likely to be mediated by membrane components, which have been shown to inhibit DNA synthesis in endothelial cell cultures.54

Coronary collateral growth

I. Cellular and biochemical factors implicated stimulation of collateral growth and angiogenesis

Table

Cellular elements Loss of contact inhibition Pericyte dropout Monocyte mitogen delivery Platelet byproduct “showering” Extracellular matrix Regulation of growth factor-receptor Formation of luminal structures

489

in

interactions

Growth factors Non-Heparin binding Small: Tumor-derived growth factor Rat carcinoma angiogenic factor Copper Prostaglandins (Es) Large: Wound fluid factor Angiogenin Heparin binding Acidic fibroblast growth factor (aFGF, HBGF-1) Basic fibroblast growth factor (bFGF, HBGF-2) Transforming growth factors (TGFu, TGFp) Platelet-derived growth factor (PDGF) HEGF,

Heparin-binding growth factor.

Pericytes, which surround mature vessels, notably disappear during neovascular development in many tissues during pathologic and reparative growth. Endothelial cell proliferation is inhibited in cell culture with pericytes.55 This inhibition is not imparted by a pericyte extract, implying that a cell-to-cell interaction must be responsible for this effect.14 Monocytes adhere to endothelial cells and invade the walls of developing collateral vessels in dogs.56y57 Their role may be in delivery of monocyte-derived mitogenic growth factors (for example, tumor necrosis factor, platelet-derived growth factor) to specific sites as required for cellular proliferation. Cell-to-cell interactions, complement, or other activating factors may also be involved. l2 An intriguing observation has been made regarding the process of monocyte invasion and associated subintimal thickening. These events are remarkably similar to the early stages of atherosclerotic plaque development.12 Both processes involve endothelial damage and repair, growth factor elaboration, and smooth muscle cell proliferation. Since platelets produce a number of known growth factors,58-60 a significant role in collateral growth and transformation has been suspected. However, platelets are rarely found in collateral vessels themselves.56s57 Platelet aggregation, adherence, and vessel wall invasion occur primarily in regions of damaged vascular endothelium. Schaper et a1.61 sug-

490

Kass, Kotler,

and Yazdanfar

gest that perhaps platelet aggregation at the site of the coronary lesion may result in the “showering” of the microvasculature with platelet by-products. The extracellular matrix of the surrounding cells also appears to be involved in regulation of proper neovascular growth and development. This matrix of glycoprotein cellular projections may help control endothelial cell response to vascular injury.62 It may help regulate growth factor activity by prevention of interaction with cell receptors under normal conditions, or by presentation of growth factors to cell receptors under conditions favoring growth.14 The extracellular matrix also seemsto be important in the formation of tubelike luminal structures.63 Growth factors. Over the past 10 years there have been many different biochemical factors identified that have the capacity to stimulate proliferation or growth-related changes in vascular cells. The numerous factors and the wide variety of tissues from which these have been isolated probably reflects their functional diversity, with the need for specific systems of growth and repair in different organs. A classification system of these factors has been developed based primarily on their ability to bind to heparin. Non-heparin binding growth factors have been further classified according to size. Small factors ( 66 Copper-deficient rabbits were unable to respond to angiogenic stimulation in one study.70 Prostaglandin Ez induces new vessel growth in the chick chorioallantoic membrane, an assay often used for angiogenic activity. 73Large non-heparin binding growth factors include a wound fluid factor and angiogenin. Wound fluid factor is released from hypoxic macrophages and stimulates endothelial cell migration but not proliferation. 74Angiogenin is a polypeptide that acts as a potent stimulator of angiogenesis in vitro. It was first isolated from human adenocarcinema cells, but has subsequently been identified in normal human sera.14It exhibits some ribonuclease activity75 and has significant genetic sequence homology with pancreatic ribonucleases.75 Although angiogenin does stimulate vessel growth in laboratory assays, its mechanism of action is still unclear, since it does not stimulate endothelial cell migration or proliferation in vitro.14, 75 Heparin-binding growth factors (HBGFs) include a family of polypeptides that have a high affinity for

American

February 1992 Heart Journal

the glycosaminoglycan moiety of heparin. These factors were originally purified by taking advantage of this affinity. They directly stimulate proliferation and migration of endothelial cells and fibroblasts, resulting in new vessel growth.76p77Anionic HBGFs are found primarily in neural tissues, while cationic HBGFs are found in most others. HBGFs include acidic fibroblast growth factor (also referred to as aFGF or HBGF-1) and basic fibroblast growth factor (bFGF or HBGF-S), which have been characterized extensively. Transforming growth factors (TGFs) are another group of peptides that specifically alter characteristics of mature cells, allowing for cellular proliferation. For example, a TGF may cause fibroblasts to lose contact inhibition in vitro, allowing cells to pile up and proliferate. 78TGF-a and TGF-0 have been isolated from various tissues. TGF-@ may act as a regulator of vessel growth depending on the cellular milieu in which it is functioning. When injected into a wound, TGF-P stimulates endothelial cell growth, resulting in highly vascular granulation tissue.75 When added to endothelial cells in culture however, TGF-/3 inhibits proliferation. Other growth factors that have been noted to enhance vessel growth include platelet-derived growth factor (PDGF) and some other tumor-derived growth factors (TDGFs). PDGF stimulates smooth muscle cell proliferation in vitro, but does not stimulate endothelial cell proliferation.7gy 8o Angiogenic growth factors have been isolated from cardiac tissue. Kumar et a1.81initially purified a small TDGF from infarcted human myocardium that could stimulate endothelial cell proliferation in cell culture. Galloway et a1.82extracted an endothelial cell growth factor from ischemic rabbit myocardium. This factor was shown to promote DNA synthesis as well as endothelial cell proliferation. The amount of factor extracted was proportional to the extent of myocardial injury induced. D’Amore and Thompson14 later described an HBGF in normal human atria1 tissue that could also be extracted from canine cardiac tissue. This factor promoted DNA synthesis and endothelial cell proliferation, cross-reacted with other HBGFs, and was extracted in larger quantities under conditions of increased myocardial injury. More recently, other HBGFs have been identified and characterized in cardiac tissue. Quinkler et a1.83 purified acidic and basic fibroblast growth factor as well as a truncated form of angiogenic fibroblast growth factor from canine, bovine, and porcine hearts. Casscellset alB4 reported specific characteristics and

VoIum~ Number

123 2

localization of acidic and basic fibroblast growth factors isolated from human heart specimens. These factors were found primarily in endothelial cells and cardiac myocytes, but not in smooth muscle cells. Immunohistochemical techniques have been used to further localize acidic fibroblast growth factor to within myocardial cell nuclei.61 It should be emphasized that the presence of neovascular growth factors in cardiac tissue does not necessarily mean that their normal function is to induce angiogenesis in response to ischemia or hypertrophy. These factors have also been isolated from cardiac tissue of species that are rarely affected by these pathologic processes. Their function may be entirely related to cardiac embryologic development, or to other unrelated endocrine,85 neurotropic,86 or vasoactive87 properties of these molecules. The fact that many of these factors have rather potent mitogenie effects, however, strongly suggests that they play a key role in angiogenesis and collateral development. Mechanism of growth factor action. Despite the fact that growth factors are normally present in heart and other tissues at all times, vascular growth and development do not occur unless stimulated. This implies that a mechanism must exist to regulate growth factor activation. It has been suggested that ischemia may induce changes that allow growth factors to come in contact with cellular receptors. For example, a change in the integrity of the extracellular matrix may expose receptors or free stored growth factors.61 Another proposed mechanism involves the upregulation of cellular growth factor receptors in response to an activator released during ischemia.12 It is unlikely that most of the currently identified growth factors would be the initiating ischemiarelated mitogenic agent. The facts that fibroblast growth factors have been identified intracellularly and that their coding genes do not contain a sequence that facilitates crossing of the cell membrane make it unlikely that they would be available to react with membrane receptors unless enough damage were done to release them from within the ce11.61This may occur with infarction, but would be unlikely to occur to a great extent among ischemic cells, in which the cell membrane is usually left intact. Genetic coding sequences for specific growth factors have been elucidated, making it possible to study transcription of growth factors under various conditions and to determine where and when these growth factors are synthesized. Schaper et al. have employed molecular biologic techniques extensively in experi-

Coronary collateral

growth

491

TUNNEL

Fig. 2. Experimental preparation of internal mammary artery implantation in proximity to the distal left anterior descending (LAD) artery. The LAD is gradually occluded

proximally by an Ameroid constrictor. (Reproduced with permissionfrom Unger EF, Sheffield CD, Epstein SE. Circulation 1990;82:1449-66.)

ments that have revealed a number of important points in the mechanism of angiogenesis in coronary collateral development. Northern blot complementary deoxyribonucleic acid (cDNA) hybridization and reverse transcription amplification techniques have been used to demonstrate an increased transcription of acidic fibroblast growth factor and TGF-@ in collateralized myocardium compared with normal myocardium.61 Thus a link between growth factor activation and collateral development has been established. In situ hybridization of cDNA to messenger ribonucleic acid (RNA) in tissue sections has shown that growth factors in collateralized myocardium are primarily localized in vascular wall cells and not within myocardial cells.61 This appears to be an unexpected finding, since endothelial cells are much more resistant to ischemia than the high oxygen-requiring myocytes.88 It suggests that ischemic myocytes must somehow signal vascular cells to begin transcription of growth factors. Schaper et a161 have proposed a mechanism of collateral growth based on the above findings. The

492

Kass, Kotler, and Yazdanfar

American

February 1992 Heart Journal

Fig. 3. Arteriogram of internal mammary artery (IMA) by contrast injection through a silicone rubber tube in the distal IMA, demonstrating newly formed collateral vessels between the IMA and a diagonal branch of the left anterior descending (LAD) artery that has been occluded proximally by an Ameroid constrictor. The arteriogram was taken 8 weeks after IMA implantation. (Reproduced with permission from Unger EF, Sheffield CD, Epstein SE. Circulation 1990:82:1449-66.)

process begins with episodic ischemia resulting from progressive coronary stenosis. These episodes cause the release or activation of a yet unidentified ischemia-related mitogen activator. This activator then binds to endothelial cell receptors and initiates fibroblast growth factor transcription. Endothelial cell mitosis is stimulated, with subsequent production and activation of other growth factors, including PDGF, which stimulates smooth muscle cell mitosis, and TGF-/I, which aids in differentiation. Monocytes and platelets attracted by stimulated endothelial cells may also provide other growth factors, including the angiogenic tumor necrosis factor. The process by which the ischemic event initiates the cascade of growth factor activation remains to be determined. Schaper et aL61are currently attempting to use sophisticated molecular biologic cloning techniques to isolate a possible peptide that could act as the ischemia-related mitogen activator. Adenosine and nicotinic acid have both been suggested to fulfill this role as well. Both of these molecules may be available in greater supply during ischemia, when adenosine triphosphate (ATP) and nicotinamide-

Fig. 4. Synthetic “organoid” derived from a meshwork of fine polytetrafluoroethylene fibers coated with collagen and an angiogenic growth factor that has been implanted in the peritoneal cavity of a rat. Vessels from the organoid extend to the rat’s natural liver (top panel). A vascular network of numerous small vessels develops after implantation (middle panel). Cross-sectional view of the newly developed vascular tissue (bottom panel) reveals multiple channels lined by endothelial cells and surrounded by layers of smooth muscle cells. (Reproduced with permission from Thompson JA, Anderson KD, DiPietro JM, et al. Science 1988;241:1349-52.)

Volume Number

123 2

adenine dinucleotide (NAD) are catabolized to their fullest extent. Some angiogenic activity has been noted in cell culture with these substances.sgrgO Long-term infusion of adenosine has been reported to increase capillary density in rabbit hearts.g1 Dipyridamole infusion, which increases adenosine availability, has also been shown to have a similar effect in rats.g2 Ingestion of high doses of dipyridamole in dogs, however, does not appear to potentiate collateral growth.61 Endothelial cells also have a great capacity to inactivate adenosine,g3 which makes it difficult to believe that this could be the messenger that stimulates endothelial cell growth factor transcription. FUTURE CONSIDERATIONS

The ultimate goal of research in this area is nothing less than to obtain control over vascular growth and development. This would allow for both inhibition of pathologic vascular growth that occurs in many diseases and for enhancement of reparative and collateral vascular growth. Acceleration of myocardial collateral growth is a more foreseeable goal over the next decade. Agents currently under investigation may indeed help mitigate against infarction by helping to delay infarct completion, improve thrombolytic therapy results, reduce reperfusion injury, preserve myocardial viability, and improve remodeling. Indirect evidence of collateral enhancement leading to preservation of ventricular function in acute infarction is already becoming available. A recent studyg4 documented an increase in angiographic collateral visualization with some associated improvement in regional and global ventricular function among a small number of patients with acute infarction who were treated with heparin. Heparin has also been shown to enhance collateral growth in dogs subjected to repeated brief coronary occlusions. g5 The mechanism of this effect is not clear, but it may in part reflect an increase in the availability or activity of HBGFs. A different approach toward revascularization utilizing angiogenic growth factors is being explored by Unger et al. g6,g7 The goal of their experiments has been to see if growth factors can enhance collateral development between an unobstructed epicardially implanted artery and the diseased native circulation. In a canine model, functional anastomotic channels were shown to develop between an implanted internal mammary artery and a collateral-dependent Ameroid-obstructed left anterior descending coronary artery (Figs. 2 and 3). Infusion of heparin into

Coronary collateral growth

493

the internal mammary artery has subsequently been shown to enhance development. This model has also paved the way for future studies using locally targeted specific angiogenic agents. Direct application or continuous infusion of the acidic fibroblast growth factor aFGF to collateral-dependent myocardium has also been shown to induce smooth muscle cell hyperplasia in vivo in a dog mode1.g8 Another major hurdle that remains to be crossed is the limitation of available flow via typical coronary collaterals. Perhaps more in-depth research into mechanisms of angiogenesis will allow further understanding of how normal and even pathologic vessels can grow to accommodate greater blood flow. Such large capacity vessels certainly develop in many types of tumors. A particularly interesting and promising application of this research is in the area of potential artificial bypass graft materials. Searching for a method of delivery for genetically engineered substances, Thompson et a1.gglloo and others have developed a method of inducing neovascular growth in a meshwork of polytetrafluoroethylene* fibersggp loo (Fig. 4). This neovascular “organoid” has the capacity to adsorb to the surface of an organ and become continuous with its blood supply when implanted in vivo.ioo Applications in coronary disease are currently under investigation. As the understanding of the mechanisms involved in collateral growth and development progresses over the coming years, insights into other problems can be expected as well, particularly in regard to the development of restenosis, the phenomena of myocardial hibernation and stunning, and the pathophysiology of atherosclerosis. It is clear that the “great potential of collateral development” will become more well recognized as we begin to realize that goal. *Gore-tex vascular graft is a registered ciates Inc., Elkton, Md.

trade name of W. L. Gore & Aaso-

REFERENCES

1. Webster J, Moberg C, Rincof G. Natural history of severe proximal coronary artery disease as documented by coronary cineangiography. Am J Cardiol 1974;33:195-200. 2. Williams DO, Amsterdam EA, Miller RR, Mason DT. Functional significance of coronary collateral vessels in patients with acute myocardial infarction: relation to pump performance, cardiogenic shock, and survival. Am J Cardiol 1976; 37:345-51. 3. Saito Y, Yasuno M, Ishida M, et al. Importance of coronary collaterals for restoration of left ventricular function after intracoronary thrombolysis. Am J Cardiol 1985;55:1259-63. 4. Cohen M, Rentrop KP. Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary ar-

494

5. 6.

7.

8. 9.

10. 11. 12. 13.

14. 15. 16.

17. 18. 19.

20.

21.

22.

23.

24.

Kass, Kotler,

and Yazdanfar

tery occlusion in human subjects: a prospective study. Circulation 1986;74:469-76. Hansen JF. Coronary collateral circulation: clinical significance and influence on survival in patients with coronary artery occlusion. AM HEART J 1989;117:290-5. Rentrop KP, Blanke H, Karsch KR, Rutsch W, Schartl M, Merx W, Dorr R, Mathey D, Kuck K. Changes in left ventricular function after intracoronary streptokinase infusion in clinically evolving myocardial infarction. AM HEART 3 1981;102:1188-93. Rentrop KP, Feit F, Sherman W, Stecy P, Hosat S, Cohen M, Rev M. Ambrose J. Nachamie M. Schwartz W. Cole W. Perdoncin’R, Thornton JC. Late thrdmbolytic therapy preserves left ventricular function in patients with collateralized total coronary occlusion: primary end point findings of the second Mount Sinai-New York University Reperfusion Trial. J Am Co11 Cardiol 1989;14:58-64. Rentrop KP, Feit F, Thornton JC, et al. The protective potential of collaterals depends on the time of their development [Abstract]. J Am Co11 Cardiol 1990;15:202A. Sabri MN, DiSciascio G, Cowley MJ, Alpert D, Vetrovec GW. Coronary collateral recruitment: functional significance and relation to rate of vessel closure. AM HEART J 1991:121:87680. Marcus M. The coronary circulation in health and disease. New York: McGraw-Hill. 1983:221-41. Schaper W. The collateral circulation of the heart. New York: Elsevier, 1971. Schaper W, Gorge G, Winkler B, Schaper J. The collateral circulation of the heart. Prog Cardiovasc Dis 1988;31: 57-77. Schaper W, Flameng W, Winkler B, Wiisten B, Ttirrschmenn W, Neugebauer G, Carl M. Quantitation of collateral resistance in-acute and chronic experimental coronary occlusion in the doe. Circ Res 1976:39:371-7. D’Amore-PA, Thompson ‘RW. Mechanisms of angiogenesis. Annu Rev Physiol 1987;49:453-64. Folkman J, Haudenschild C. Angiogenesis in vitro. Nature 1980;288:551-6. Schwartz H, Leiboff RH, Bren GB, Wasserman AG, Katz RJ, Varahese PJ. Sokil AB. Ross AM. Temnoral evolution of the h&an coronary collateral circulation after myocardial infarction. J Am Co11 Cardiol 1984;4:1088-93. Nit&erg WD, Nath HP, Rogers WJ, Hood WP, Whitlow PL, Reeves R, Baxley WA. Collateral flow in patients with acute myocardial infarction. Am J Cardiol 1985;56:729-36. Fujita M, Sasayama S, Ohno A, Nakajima H, Asanoi H. Importance of angina for development of collateral circulation. Br Heart J 1987;57:139-43. Rentron KP. Cohen M. Blanke H. et al. Chanees in collateral channel filling immediately after controlled coronary artery occlusion by angioplasty balloon in human subjects. J Am Co11 Cardiol 1985;5:587-92. Franklin D, McKnown D, McKnown M, et al. Development and regression of coronary collaterals induced by repeated, reversible ischemia in dogs [Abstract]. Fed Proc 1981;40: 339. Schaper W, W&ten B. Collateral Circulation. In: Schaper, W ed. The pathophysiology of myocardial perfusion. Amsterdam: Elsevier, North-Holland Biomedical Press, 1979: chapter 13. Mohri M, Tomoike H, Noma M, Inoue T, Hisano K, Nakamura M. Duration of ischemia is vital for collateral development: repeated brief coronary artery occlusions in conscious dogs. Circ Res 1989;64:287-96. Zoll PM, Wessler S, Schlesinger MJ. Interarterial coronary anastomoses in the human heart, with particular reference to anemic and relative cardiac anoxia. Circulation 1951;4:797815. Schlesinger MJ. An injection plus dissection study of coro-

American

25. 26. 27. 28. 29.

30. 31. 32. 33. 34.

35.

36.

37. 38. 39. 40. 41. 42.

43.

44. 45. 46. 47.

February 1992 Heart Journal

nary artery occlusions and anastomoses. AM HEART J 1938; 15~528-68. Allison R, Rodriquez F, Higgins E. Clinicopathologic correlations in coronary atherosclerosis. Circulation 1963;27:17084. Helfant R, Kemp H, Gorlin R. Coronary atherosclerosis, coronary collaterals, and their relation to cardiac function. Ann Intern Med 1970;73:189-93. Bishop S, White F, Bloor C. Regional myocardial blood flow during acute myocardial infarction in the conscious dog. Circ Res 1976;38:429-38. Lauries W. Woods J. Anastomosis in the coronary circulation. Lancet 1958;2:812. Pepler W, Meyer B. Interarterial coronary anastomoses and coronary arterial pattern: a comparative study of South African Bantu and European hearts. Circulation 1960;22: 14-24. Eckstein R. Development of interarterial coronary anastomoses by chronic anemia. Circ Res 1955;3:306-10. Scheel KW, Brody DA, Ingram LA, et al. Effects of chronic anemia on the coronary and coronary collateral vasculature in dogs. Circ Res 1976;38:553-9. Nolewajka AJ, Kostuk WJ, Rechnitzer PA, et al. Exercise and human collateralization: an angiographic and scintigraphic assessment. Circulation 1979;60:114-29. Sim DN, Neil1 WA. Investigation of the physiological basis for increased exercise threshold for angina pectoris after phvsical conditioning. J Clin Invest 1974:54:763-70. Verani MS, Hartung-GH, Hoepfel-Harris. J, et al. Effects of exercise training on left ventricular performance and myocardial perfusion in patients with coronary artery disease. Am J C-ardiol 1981;47:798-803. Heaton WH. Marr KC. Caourro NL. et al. Beneficial effect of physical training on blood flow to myocardium perfused by chronic collaterals in the exercising dog. Circulation 1978; 57:575-8. Cohen MV, Steingart RM. Exercise thallium-201 scintigraphy in dogs: effects of long-term coronary occlusion and collateral development on early and late scintigraphic images. Circulation 1985;72:881-91. Eckstein RW. Effect of exercise and coronary artery narrowing on coronary collateral circulation. Circ Res 1957;5:230-5. Neil1 WA. Oxendine JM. Exercise can promote coronary collateral development without improving perfusion of ischemic myocardium. Circulation 1979;60:1513-9. Scheel KW, Ingram LA, Wilson JL. Effects of exercise on the coronary and collateral vasculature of beagles with and without coronary occlusion. Circ Res 1981;48:523-30. Schaper W. Influence of physical exercise on coronary collateral blood flow in chronic experimental two-vessel occlusion. Circulation 1982;65:905-12. Aygen M. Collateral circulation and regional myocardial function. Bib1 Cardiol 1977;36:136-40. Conner J, LaCamera F, Swanick E, Oldhan M, Holzaepfel D, Lvczkowskvi 0. Effects of exercise on coronary collateralizat&i-angiographic studies of six patients in a-supervised exercise program. Med Sci Sports 1976;8:145-51. Ferguson R, Petitclerc R, Choquette G, Chaniotis L, Gauthier P, Xeriot R, Allard C, Jankourski L, Campeau L. Effect of physical training on treadmill exercise capacity, collateral circulation, and progression of coronary disease. Am J Cardiol 197$34:764-g. Barmeyer J. Physical activity and coronary collateral development. Adv Cardiol 1976;18:104-12. Marcus M. The coronary circulation in health and disease. New York: McGraw-Hill, 1983:221-41. Baroldi G, Scomazzoni G. Coronary circulation in the normal and pathologic heart. Washington, DC: Office of the Surgeon General. Department of the Army, 1967:47. Baroldi G, Mantero 0, Scomazzoni G. The collaterals of the

Volume Number

48. 49.

50.

51. 52.

53.

54.

55.

56.

57.

58. 59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

123 2

coronary arteries in normal and pathologic hearts. Circ Res 1956;4:223-9. Gregg DE. Coronary circulation in health and disease. Philadelphia: Lea & Febiger, 1950. Schaper W. Tangential wall stress as a molding force in the development of collateral vessels in the canine heart. Experientia (Basel) 1967;23:595-8. Pasyk S, Schaper W, Schaper J, et al. DNA synthesis in coronary collaterals after coronary artery occlusion in the conscious dog. Am J Physiol 1982;242:H1031-7. Herman IM, Pollard TD, Wong AJ. Contractile proteins in endothelial cells. Ann NY Acad Sci 1983;401:50-60. White GE, Gimbrone MA Jr, Fujiwara K. Factors influencing the expression of stress fibers in vascular endothelial cells in situ. J Cell Biol 1983;97:416-24. Scheel KW, Rodriguez RJ, Ingram LA. Directional coronary collateral growth with chronic circumflex occlusion in the dog. Circ Res 1977;40:384-90. Heimark RL, Schwartz SM. The role of membrane-membrane interactions in the regulation of endothelial cell growth. J Cell Biol 1985;100:1934-40. Cracker DJ, Murad TM, Geer JC. Role of the pericyte in wound healing. An ultrastructural study. Exp Mol Path01 1970;13:51-65. Schaper J, Borgers M, Schaper W. Ultrastructure of ischemia-induced changes in the precapillary anastomotic network of the heart. Am J Cardiol 1972;29:851-9. Schaper J, Koenig R, Franz D, Schaper W. The endothelial surface of growing coronary collateral arteries: intimal margination and diapedesis of myocytes: a combined SEM and TEM study. Virchows Arch (A) 1976;370:193-205. Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell 1986;46:155-69. Heldin CH, Johnsson A, Wennegren S, Wernstedt C, Betsholtz C, Westermark B. A human osteosarcoma cell line secretes a growth factor structurally related to a homodimer of PDGF A-chains. Nature 1986;319:511-4. Sporn MB, Roberts AB, Wakefield LM, Assoian RK. Transforming growth factor-beta: biological function and chemical structure. Science 1986;233:532-4. Schaper W, Sharma HS, Quinkler W, Markert T, Wiinsch M, Schaper J. Molecular biologic concepts of coronary anastomoses. J Am Co11 Cardiol 1990;15:513-8. Young WC, Herman IM. Extracellular matrix modulation of endothelial cell shape and motility following injury in vitro. J Cell Sci 1985;73:19-32. Madri JA, Williams SK. Capillary endothelial cell structures: phenotypic modulation by matrix components. J Cell Biol 1983;97:153-65. Fenselau A, Watt S, Mello RJ. Tumor angiogenesis factor. Purification from the Walker 256 rat tumor. J Biol Chem 1981;256:9605-11. Phillips P, Kumar S. Tumour angiogenesis factor (TAF) and its neutralisation by a xenogeneic antiserum. Int J Cancer 1979;23:82-8. Shahabuddin S, Kumar S, West D, Arnold F. A study of angiogenesis factors from five different sources using a radioimmunoassay. Int J Cancer 1985;35:87-91. Hannan GN, McAuslan BR. Modulation of synthesis of specific proteins in endothelial cells by copper, cadmium, and disulfiram: an early response to an angiogenic inducer of cell migration. J Cell Physiol 1982;111:207-12. Lobb R, Sasse Y, Sullivan R, Shing Y, D’Amore P, et al. Purification and characterization of heparin-binding endothelial cell growth factors. J Biol Chem 1986;261:1924-8. Raju KS, Allesandri G, Ziche M, Gullino PM. Ceruloplasmin, copper ions, and angiogenesis. J Nat1 Cancer Inst 1982;69: 1183-8. Ziche M, Jones J, Gullino P. Role of prostaglandin El and copper in angiogenesis. J Nat1 Cancer Inst 1982;69:475-82.

Coronary collateral

growth

495

71. Castellot JJ Jr, Karnovsky MJ, Spiegelman BM. Differentiation-dependent stimulation of neovascularisation and endothelial cell chemotaxis by 3T3 adipocytes. Proc Nat1 Acad Sci USA 1982;79:5597-601. 72. Castellot JJ Jr, Kambe AM, Dobson DE, Spiegelman BM. Heparin potentiation of 3T3-adipocyte stimulated angiogenesis: mechanisms of action on endothelial cells. J Cell Physiol 1986,127:323-g. 73. Form DM, Auerbach R. PGE2 and angiogenesis. Proc Sot Exp Biol Med 1983;172:214-8. 74. Banda MJ, Knighton DR, Hunt TK, Werb Z. Isolation of a nonmitogenic angiogenesis factor from wound fluid. Proc Nat1 Acad Sci USA 1982;79:7773-7. 75. Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235:442-7. 76. Lobb RR, Alderman EM, Fett JW. Induction of angiogenesis by bovine brain derived class 1 heparin-binding growth factor. Biochemistry 1985;24:4869-73. 77. Shing Y, Folkman J, Haudenschild C, Lund D, Crum R, Klagsbrun M. Angiogenesis is stimulated by a tumor-derived endothelial cell growth factor. J Cell Biochem 1986;29:27587. 78. DeLarco JE, Todaro GJ. Sarcoma growth factor (SGF): specific binding to epidermal growth factor (EGF) membrane receptors. J Cell Physiol 1980;102:267-77. 79. Schreiber AB, Kenney J, Kowalski WJ, et al. Interaction of endothelial cell growth factor with heparin: Characterization by receptor and antibody recognition. Proc Nat1 Acad Sci 1985;82:6138-42. 80. Bowen-Pope DF, Ross R. Platelet-derived growth factor. II. Specific binding to cultured cells. J Biol Chem 1982;257:516171. 81. Kumar S, Shahabuddin S, Haboubi N, et al. Angiogenesis factor from human myocardial infarcts. Lancet 1983;2:364-8. 82. Galloway AC, Pelletier R, D’Amore PA. Do ischemic hearts stimulate endothelial cell growth? Surgery 1984;96:435-9. 83. Quinkler W, Maasberg M, Bemotat-Danielowski S, Liithe N, Sharma HS, Schaper W. Isolation of heparin binding growth factors from bovine, porcine, and canine hearts, Eur J Biochem 1989;181:67-73. 84. Casscells W, Speir E, Sasse J, Klagsbrun M, Allen P, Lee M, Calvo B, Chiba M, Haggroth L, Folkman J, Epstein SE. Isolation, characterization, and localization of hem&-binding growth factors in the heart. J Clin Invest 199&85:433-41. 85. Baird A, Mormede P, Ying SY, Wehrenberg WB, Ueno N, Ling N, Guillemin B. A non-mitogenic pituitary function of fibroblast growth factor: regulation of thyrotropin and prolactin secretion. Proc Nat1 Acad Sci USA 1985:82:5545-Q. 86. Walicke P, Cowan WM, Ueno N, Baird A, Guillemin R. Fibroblast growth factor promotes survival of dissociated hippocampal neurons and enhances neurite extension. Proc Nat1 Acad Sci USA 1986;83:3012-6. 87. Berk BC, Alexander RW, Brock TA, Gimbrone MA Jr, Webb RC. Vasoconstriction: a new activity for platelet-derived growth factor. Science 1986,232:87-90. 88. Schaper J, Schaper W. Time course of myocardial necrosis. Cardiovasc Drug Ther 1988,2:17-25. 89. Swam J, et al. J Mol Cell Cardiol (In press) 90. Meininger CJ, Schelling ME, Granger HJ. Adenosine and hypoxia stimulate proliferation and migration of endothelial cells. Am J Physiol 1988;255:H554-62. 91. Hudlicka 0. Growth of capillaries in skeletal and cardiac muscle. Circ Res 1982;50:451-61. 92. Mall G, Mattfeldt T, Volk B. Ultrastructural morphometric study on the rat heart after chronic ethanol feeding. Virchows Arch [A] 1980;389:59-77. 93. Nees S, Gerlach E. Adenosine nucleotide and adenosine metabolism in cultured coronary endothelial cells: formation and release of adenine compounds and possible functional implications. In: Berne RMK, Rall TW, Rubio R, eds. RegI--

~-

--

496

94.

95.

96.

97.

Kass, Kotler,

and Yazdanfar

American

ulatory function of adenosine. Boston: Martinus Nijhoff, 1983:347-60. Ejiri M, Fujita M, Miwa K, Hirai T, Yamanishi K, Sakai 0, Ishizaka S, Sasayama S. Effects of heparin treatment on collateral development and regional myocardial function in acute myocardial infarction. AM HEART J 1990;119:248-53. Fujita M, Mikuniya A, Takahashi M, Gaddis R, Hartley J, McKown D, Franklin D. Acceleration of coronary collateral development by heparin in conscious dogs. Jpn Circ J 1987;51:395-402. Unger EF, Sheffield CD, Epstein SE. Creation of anastomoses between an extracardiac artery and the coronary circulation: proof that myocardial angiogenesis occurs and can provide nutritional blood flow to the myocardium. Circulation 1990;82:1449-66. Unger EF, Sheffield CD, Epstein SE. Effect of heparin on the

BOUND

VOLUMES

AVAILABLE

formation of anastomoses between an extracardiac artery and the myocardial circulation in a canine model [Abstract]. Circulation 1990;82(suppl):III-377. 98. Banai S, Shrivastav S, Casscells W, Jaklitsch MT, Shou M, Unger EF. Immunohistochemistry of normal and infarcted canine myocardium after application of acidic fibroblast growth factor to the collateral-dependent territory [Abstract]. Circulation 1990;82(suppl):III-378. 99. Thompson JA, Haudenschild CC, Anderson KA, DiPietro JM, Anderson WF, Maciag T. Heparin-binding growth factor 1 induces the formation of organoid neovascular structures in vivo. Proc Nat1 Acad Sci USA 1989867928-32. 100. Thompson JA, Anderson KD, DiPietro JM, Zwiebel JA, Zametta M, Anderson WF, Maciag T. Site-directed neovesse1 formation in vivo. Science 1988,241:1349-52.

TO SUBSCRIBERS

Bound volumes of the AMERICAN HEART JOURNAL are available to subscribers (only) for the 1992 issues from the Publisher at a cost of $57.00 for domestic, $76.99 for Canadian, and $75.00 for international subscribers for Vol. 123 (January-June1 and Vol. 124 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146, USA, phone (600)325-4177, ext. 4351, or (3141453-4351. Subscriptions subscription.

must

be

in force

to qualify.

Bound

volumes

February 1992 Heart Journal

are

not

available

in place

of a regular

Journal