Cardiovascular Research

Cardiovascular Research 2000 45(1):220-223; doi:10.1016/S0008-6363(99)00332-6
© 2000 by European Society of Cardiology

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Copyright © 2000, European Society of Cardiology

Quo vadis collateral blood flow?

A commentary on a highly cited paper

Wolfgang Schaper^*

Max Planck Institute for Clinical and Physiological Research, Department of Experimental Cardiology, Benekestr. 2, D-61231 Bad Nauheim, Germany

^* Tel.: +49-6032-705-402; fax: +49-6032-705-419

KEYWORDS Blood flow; Collateral circulation; Coronary circulation; Coronary disease; Infarction; Ischemia

	1 Introduction

Top 1 Introduction 2 Where do we... 3 Angiogenesis and... 4 Summary References

 
The highly cited landmark paper by the Hearse–Yellon group from the year 1987 [1] still stands out for its thoroughness and stringency of approach. Above all, the information contained in it is still valid and is not superceded by new results obtained by more modern methods. On the contrary, ‘modern’ methods in hemodynamics often lack the precision of the gold standards that we were used to. Blood flow studies in animals are now often performed with the less rigorous clinical techniques. Part of the problem is that the more precise and more sensitive, older methods have become so expensive (radioactive waste and cadaver disposal) that their use has become prohibitive.

The strength of the Maxwell–Hearse–Yellon paper is that collateral blood flow was measured over a wide range of the mammalian kingdom using the same method thereby making the results comparable. The objective was to obtain a more rational basis for experiments dealing with ischemia and its modulation and to come to a more meaningful selection of the right animal model for the question to be tested: rats, rabbits and pigs that have practically no collateral flow are well suited for ischemia tolerance studies. Dogs, cats and guinea pigs with their variable and often sizeable collateral flow are well suited for studies of vascular adaptation to ischemia.

Another strong point of the Maxwell–Hearse–Yellon paper was the observation that the borders of perfusion are sharply delineated even in species with good collateral flow (with the exception of the guinea pig). This put an end to the discussion whether infarcts develop in a ‘bull's-eye’ fashion where a borderzone of intermediate blood flow values expands toward the periphery [2]. The ‘wavefront’ hypothesis by Reimer and Jennings [3] had anticipated this finding, showing that infarcts start in the subendocardium and move wave-front like toward the epicardium along the edges of the perfusion territory.

As always, the paper in question had its predecessors. Our group had presented similar results in rats, rabbits, pigs and dogs at a meeting organized by Hearse and Yellon and our results were published in the proceeding book of that conference [4]. We were elated by the fact that the Hearse–Yellon group eventually confirmed our previous results. This is the way that science should work but often doesn’t.

Our studies were done to find out the major determinants of infarct size and apart from the size of the vascular territory perfused by the occluded artery (1) and the duration of occlusion (2), infarcts were significantly determined by collateral blood flow (3). With the exception, of course, of those species that had no collaterals, time seemed to be the most important determinant.

About the same time that the Hearse–Yellon paper appeared, a fourth determinant of infarct size was discovered. Ischemia tolerance can be manipulated by ischemic preconditioning [5]. We had shown earlier that in animals with significant collateral flow myocardial oxygen consumption at the moment of occlusion constituted the 5th determinant of infarct size [6].

The insight, that acute occlusion of a coronary artery did not cause an ‘acute M.I.’ but rather a state of myocardial ischemia that, for a certain interval, caused a reversible type of damage, was not lost on the clinicians. They realized that time is of the utmost importance when a coronary thrombosis had to be lysed [7]. To illustrate the importance of time in thrombolysis our diagram of infarct size versus time was furnished by the manufacturer with each vial of recombinant tPA (of course without remuneration to our lab).

To put the new knowledge of collateral blood flow into clinical practice was and still is difficult. Collateral blood vessels, if present, do not significantly react to drugs and since they are close to ischemic tissue they are already maximally vasodilated when a major artery is acutely occluded. The only way we could think of making use of collateral flow about 10 years ago was to use it more efficiently by reducing the oxygen needs of the entire heart. A relatively fixed amount of flow could then reduce the degree of underoxygenation and prolong the life of the ischemic region, perhaps reducing the degree of damage and preventing it from entering the irreversible state. We reduced myocardial oxygen consumption by giving high doses of synthetic morphine-like compounds which reduced heart rate, one of the major determinants of MVO2. It was indeed possible to extend the reversible state of ischemic damage to 6 h in the dog heart [8]. It was a few years later when Gross [9] showed that it may not have been the reduction of heart rate and MVO2 alone but also and additionally the occupation of the opiate receptor which contributed to the molecular pathway of preconditioning.

Our measurements of collateral flow in the dog and our calculations of the energy resources of the dog heart at low but still physiological MVO2s arrived at the conclusion that acute coronary occlusions should not lead to infarctions in the canine heart provided the myocardium would cease to contract at relatively mild degrees of underperfusion because collateral blood flow is sufficient to cover the oxygen supply necessary for structural survival [8]. The fact that this does not occur was interpreted by us that the ischemic heart wastes much of its energy in futile attempts to contract.

	2 Where do we go from now?

Top 1 Introduction 2 Where do we... 3 Angiogenesis and... 4 Summary References

 
The Maxwell–Hearse–Yellon paper dealt with collateral flow on one hand and with the ischemia tolerance on the other. Both topics have explosively developed over the last 10 years into new branches of science. Research into collaterals has received an enormous boost with the discovery of the vascular growth factors, the first of which (FGF-1 and 2 [10,11]) were described around the time of the Yellon paper. The possibility that the rarely observed spontaneous enlargement of preexisting interconnecting arterioles due to stenosis and occlusion of a major coronary artery could be stimulated by exogenous application of growth factors or their genes to form new arteries electrified vascular medicine and appears to be the answer to arterial occlusive disease. However, much of the present day enthusiasm about VEGF and other factors may end in sobering hangovers but it is absolutely certain that progress was made in recent years and that there is more to come [12].

Ischemia tolerance has taken a similar evolution. At about the time of the Yellon paper Murry from Jennings and Reimer's group published a study on the paradoxical increase of ischemia tolerance that was observed after additional brief coronary occlusions, a phenomenon that they called ‘ischemic preconditioning’ [5]. This new field also had its predecessors in the widespread movement in the 1970s to ‘reduce infarct size’ that finally came to a halt because it was a kind of random screening lacking an underlying hypothesis and lacking adequate methods. Although ischemic preconditioning was primarily an observation, numerous hypotheses were subsequently proposed, tested (often rejected) with the purpose to bottle the genie, the active principle, and to fashion it into a drug to increase ischemic tolerance [13]. The manipulation of ischemia tolerance is an important topic especially in the era of thrombolytic therapy where the time to treatment must be as short as possible.

Both topics, i.e., ischemia control and collateral flow, still belong together because they are the two legs on which any rational therapy stands that aims at permanently salvaging potentially ischemic tissue with or without recanalization of the occluded vessel.

Increasing ischemic tolerance by employing the principles underlying ischemic preconditioning must be the primary goal to gain the time necessary for arteries to grow. This is not a totally unrealistic goal: even pig myocardium totally devoid of collateral flow can now survive a complete occlusion for 6 h if adequately pretreated. However, the cell cycle for stimulated endothelial- and smooth muscle cells, a prerequisite and hence a stumbling block for arteriogenesis, is about 18 h, and the gap that needs to be bridged by future research is a towering 12 h. On the other hand, the situation in the atherosclerotic human heart is probably less severe because of the availability of collateral blood flow.

	3 Angiogenesis and arteriogenesis

Top 1 Introduction 2 Where do we... 3 Angiogenesis and... 4 Summary References

 
It is commonly accepted today that enlargement of collateral vessels is a significant but normally underused mechanism to counteract the effects of arterial occlusions. The molecular pathways responsible for adaptive vascular growth are often loosely subsumed under the term angiogenesis. However, angiogenesis is a reserved term for the sprouting of capillaries in granulation tissue and for the vascular invasion of organs during embryogenesis [14]. Vasculogenesis is reserved for the embryonic development of blood vessels from in-situ angioblasts [15]. Collateral artery growth is best served by the term arteriogenesis [16]. Previously used terms like recapitulated vasculogenesis, made assumptions about mechanisms that are yet to be proved and all other terms, including collateral artery growth, were too wordy or did not match with the importance of the adaptation. Arteriogenesis, the growth of arteries from pre-existing arterioles, is the only relevant type of vascular growth that potentially saves limbs, hearts, brains; the growth of capillaries can never replace an occluded major artery. That arteriogenesis often prevents the worst but rarely provides enough, was previously ascribed to the lack of growth factors, i.e., the system was assumed to be supply-fed [17]. This is in contrast to the fact that growth factors are already found in the normal heart where they are stored in the extracellular matrix. They are also constitutively expressed on a low level and the mRNA of VEGF becomes stabilized under ischemic conditions [18]. Furthermore, stabilized mRNA has privileged access to the ribosome that shuts down most of its other activity under hypoxic conditions. That vascular growth still trails behind needs despite all these built-in safety precautions can have two reasons: (1) VEGF is not involved in arteriogenesis; and (2) it may have to do with the fact that arterial occlusions are mostly caused by acute thromboses that lead to necrosis and leave too little time for arteriogenesis. A role for VEGF in arteriogenesis is not established and not primarily expected because it is an endothelium-specific mitogen.

The first vascular growth factors were not discovered in growing vessels. Studies in bovine brain tissue led to the discovery of a peptide with heparin binding activity that stimulated proliferation of fibroblasts in culture, hence the name ‘fibroblast growth factor’. It was subsequently discovered that this factor was a rather broad-spectrum mitogen for most cells that were not terminally differentiated.

Although the discovery of the FGFs was immediately seen as a possibility for ‘therapeutic angiogenesis’, results of therapeutic experiments in live animals were disappointing. In the most rigorous studies employing ‘gold standard’ methods in dogs, large doses of FGF-2 increased maximal coronary flow in a model of chronic coronary occlusion from 30% of normal, a level spontaneously reached without treatment, to about 40% [19]. This means that 60% of the maximal flow remained deficient and that the degree of success was mild. Furthermore, an effect could only be achieved during a limited time window, probably relating to the availability of receptors around the time of critical stenosis. This would mean that stable angina caused by stenoses not leading to chronic ischemia are not expected to favorably react to growth factor therapy. The results obtained with the intensely studied Vascular Endothelial Growth Factor (VEGF) in animals are even more disappointing. Its effect on arteriogenesis are doubtful, it increases subintimal proliferation, it may cause angiomas and it may be atherogenic [20,21]. Many of the early successes in animal experiments were obtained with substandard methods and it was no real surprise when the first randomized double blind study with VEGF in patients with angina pectoris failed, with treated patients not better but slightly worse than with placebo [22].

It is perhaps not surprising that the simple concept of single growth factor supplementation fails because arteriogenesis is a complex morphogenic process that creates a tissue consisting of at least three different cell types and many large extracellular matrix proteins and with each component differently regulated.

A new approach was tried by our group to make use of an early observation that monocytes adhere to the endothelium of growing collateral vessels [23]. This concept was later adopted by Polverini and Leibowitz who showed that activated monocytes are angiogenic [24]. Chemoattraction of monocytes by infusion of the chemokine MCP-1 indeed increased the speed of collateral vessel growth following experimental femoral occlusion and makes it the strongest arteriogenic peptide known [25]. MCP-1 activated monocytes start to produce growth factors only at places where they are needed.

Whereas angiogenesis almost always proceeds in an environment of hypoxia, arteriogenesis does not: arteriogenesis is often remote from tissue ischemia. Arteriogenesis proceeds in an environment of inflammation and the invasion of mononuclear cells is probably caused by changes in shear stress. Arteriogenesis is mainly dominated by the invasion of monocytes and T-cells (and probably basophils and other circulating cells) that become activated and produce growth factors. The clinical future of arteriogenesis is probably linked to a better understanding of these circulating cells that will be harvested, manipulated ex vivo and reinjected.

	4 Summary

Top 1 Introduction 2 Where do we... 3 Angiogenesis and... 4 Summary References

 
This text is a commentary on the highly cited paper by Maxwell–Hearse–Yellon describing the amount of collateral blood flow in several species of mammals after coronary artery occlusion. The measurement of collateral blood flow, an academic exercise in previous times because of its invariance and the futility of changing the degree of adaptation under chronic conditions, has reached new importance because collateral vessel growth (presently called arteriogenesis) can now be manipulated with growth factors, their genes or peptides. The early successes and failures are discussed and a plea is made for the rigorous application of goldstandard methods (like in the Maxwell–Hearse–Yellon paper) to avoid disappointments in the new science of ‘therapeutic angiogenesis’.

	References

Top 1 Introduction 2 Where do we... 3 Angiogenesis and... 4 Summary References

 

1. Maxwell M.P., Hearse D.J., Yellon D.M. Species variation in the coronary collateral circulation during regional myocardial ischaemia: a critical determinant of the rate of evolution and extent of myocardial infarction. Cardiovasc Res (1987) 21:737–746.[Abstract/Free Full Text]
2. Factor S.M., Sonnenblick E.H., Kirk E.S. Histological border zone of acute myocardial infarction: islands or peninsulas? Circulation (1977) 56:III–71.
3. Reimer K.A., Lowe J.E., Rasmussen M.M., Jennings R.B. The ‘wavefront phenomenon’ of ischemic cell death. I. Myocardial infarct size versus duration of coronary occlusion in dogs. Circulation (1977) 56:786–794.[Abstract/Free Full Text]
4. Schaper W. Therapeutic approaches to myocardial infarct size limitation. Hearse D.J., Yellon D.M., eds. (1984) New York: Raven Press. 79–90.
5. Murry C.E., Jennings R.B., Reimer K.A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation (1986) 74:1124–1136.[Abstract/Free Full Text]
6. Mller K.D., Klein H., Schaper W. Changes in myocardial oxygen consumption 45 min after experimental coronary occlusion do not alter infarct size. Cardiovasc Res (1980) 14:710–718.[Abstract/Free Full Text]
7. Van der Laarse A., Vermeer F., Hermens W.T., Simoons M.L. Effect of early intracoronary streptokinase on extent and rate of development of enzymatic infarct size. Europ Heart J (1985) 6:264.
8. Schaper W., Binz K., Sass S., Winkler B. Influence of collateral blood flow and of variations in MVO2 on tissue-ATP content in ischemic and infarcted myocardium. J Mol Cell Cardiol (1987) 19:19–37.[Web of Science][Medline]
9. Schultz J.E.J., Hsu A.K., Nagase H., Gross G.J. TAN-67, a delta(1)-opioid receptor agonist, reduces infarct size via activation of G(II0) proteins and K-ATP channels. Am J Physiol (1998) 43:H909–H914.
10. Jaye M., Howk R., Burgess W., et al. Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization. Science (1986) 233:541–545.[Abstract/Free Full Text]
11. Quinkler W., Maasberg M., Bernotat-Danielowski S., et al. Isolation of heparin binding growth factors from bovine, porcine, and canine hearts. Eur J Biochem (1989) 181:67–73.[Web of Science][Medline]
12. Folkman J. Clinical applications of research on angiogenesis. N Engl J Med (1995) 333:1757–1763.[Free Full Text]
13. Cohen M.V., Downey J.M. Ischemic preconditioning: can the protection be bottled? The Lancet (1993) 342:6.
14. Risau W. Angiogenesis. Arzneimittel-Forschung/Drug Research 1994;44(I)(3a): 416–417.
15. Risau W., Flamme I. Vasculogenesis. Annu Rev Cell Dev Biol (1995) 11:73–91.[CrossRef][Web of Science][Medline]
16. Schaper W., Piek J.J., Munoz-Chapuli R., Wolf C., Ito W. Angiogenesis and cardiovascular disease. Ware J.A., Simons M., eds. (1999) New York, NY, Oxford: Elsevier Science. 159–198.
17. Schaper W., Sharma H.S., Quinkler W., et al. Molecular biologic concepts of coronary anastomoses. J Am Coll Cardiol (1990) 15:513–518.[Abstract]
18. Ikeda E., Achen M.G., Breier G., Risau W. Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem (1995) 270:19761–19766.[Abstract/Free Full Text]
19. Lazarous D.F., Scheinowitz M., Shou M., et al. Effects of chronic systemic administration of basic fibroblast growth factor on collateral development in the canine heart. Circulation (1995) 91:145–153.[Abstract/Free Full Text]
20. Banai S., Jaklitsch M.D., Shou M., et al. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation (1994) 89:2183–2189.[Abstract/Free Full Text]
21. Schwarz ER, Kioner RA. Direkte Applikation der DNA für vascular endothelial growth factor (VEGF) in die Randbereiche infarzierten Myokards induziert Angiogenese ohne Verbesserung der regionalen Myokardperfusion bei Ratten. In: Z Kardiol. 1999:675 (abstr);88 (Suppl 1)).
22. Henry TD, Annex BH, Azrin MA. et al. Double Blind, Placebo Controlled Trial of Recombinant Human Vascular Endothelial Growth Factor — The Viva Trial. In: JACC 1999:33A;384A.
23. Schaper W., Koenig R., Franz D., Schaper J. Electron Microscopy, Proc 6th Europ Congress on Electron Microscopy. Ben-Shaul J., ed. (1976) Israel: Tal International Publishing Company. 438–440.
24. Leibovich S.J., Polverini P.J., Shepard H.M., et al. Macrophageinduced angiogenesis is mediated by tumor necrosis factor-. Nature (1987) 329:630–632.[CrossRef][Medline]
25. Arras M., Ito W.D., Scholz D., et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest (1998) 101(1):41–50.

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