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The coronary collateral circulation: Genetic and environmental determinants in experimental models and humans
Journal of Molecular and Cellular Cardiology 52 (2011) 897–904
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Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Review article
The coronary collateral circulation: Genetic and environmental determinants in experimental models and humans Paul F.A. Teunissen a, Anton J.G. Horrevoets b, Niels van Royen a,⁎ a b
Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 22 June 2011 Received in revised form 25 August 2011 Accepted 12 September 2011 Available online 19 September 2011 Keywords: Arteriogenesis Angiogenesis Collateral artery growth Genetics Coronary Collateral flow Collateral circulation Experimental Human
a b s t r a c t Obstruction of coronary arteries leads to an arteriogenic response. Pre-existent collateral networks enlarge, forming large conductance arteries with the capability to compensate for the loss of perfusion due to the occlusion. Interestingly, significant differences exist between patients regarding the capacity to develop such a collateral circulation. This heterogeneity in arteriogenic response is also found between and even within animal species and it strongly suggests that next to environmental factors, innate genetic factors play a key role. The present review focuses on this heterogeneity of genetic as well as non-genetic determinants of the coronary collateral circulation. This article is part of a Special Issue entitled “Coronary Blood Flow”. © 2011 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inter- and intra-species differences in the pre-existing collateral network . . . . . . . Inter- and intra-species differences in the arteriogenic response . . . . . . . . . . . Differences in the pre-existing collateral network and the arteriogenic response in patients Non-genetic determinants of coronary collateral flow . . . . . . . . . . . . . . . . 5.1. Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Genetic determinants of collateral flow . . . . . . . . . . . . . . . . . . . . . . . 6.1. Experimental models . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: VU University Medical Center, Department of Cardiology, Room 5F-013, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel.: + 31 20 4444460; fax: + 31 20 444 2446. E-mail address: [email protected] (N. van Royen). 0022-2828/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2011.09.010
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1. Introduction In case of coronary arterial obstruction, an arteriogenic response is induced [1], leading to an arterial collateral network which sustains blood flow to the myocardium. The development of a coronary collateral circulation is associated with better preservation of left ventricular function and lower mortality rates. However, the extent of the collateral circulation, both in healthy persons as well as in patients with obstructive coronary artery disease, varies largely. Thus, whereas in some patients severe obstructive coronary artery disease is left completely unnoticed due to a well developed collateral circulation, others seem to lack the capacity to develop a sufficient collateral network. This heterogeneity is also observed between and within different animal species. The present review focuses on this heterogeneity and genetic as well as non-genetic determinants of the coronary collateral circulation.
2. Inter- and intra-species differences in the pre-existing collateral network The pre-existing collateral network varies widely between and also within species. In the last decades several animal models were used to measure collateral flow directly upon arterial obstruction. By far the most extensive study on interspecies differences in the pre-existing coronary collateral circulation has been performed by Maxwell [2]. Baseline coronary collateral flow was compared in eight different species with radiolabelled microspheres. When representing collateral flow as a percentage of flow to the non-ischemic myocardium, a large spectrum was found. For example, rabbits and pigs show a very low capacity of about 0–6% of baseline, whereas guinea pigs display compensatory collateral flow of 100% directly after arterial obstruction. Other species like dogs have a baseline collateral flow that is somewhere in between these values. These data have been confirmed in many subsequent single species studies for mice [3], rats [4], rabbits [5], pigs [6] and dogs [7] (see Table 1). Other direct comparisons of species have been performed for porcine and canine models. From these studies it was concluded that dogs have an extensive pre-existing collateral network whereas in pigs this is almost absent, leading to transmural infarction and a large percentage of animals that do not survive acute coronary occlusion [8–12]. In a recent MRI study, infarct size and the ratio of area at risk and final infarct size were compared between different species. When comparing patient data to historical animal data they surprisingly found that evolution of infarct is slowest in humans, suggesting a pre-existing collateral protective network that is even more efficient than in dogs. However, no direct measurement of collateral flow was performed. Infarct size strongly relates to collateral flow which attenuates the severity of ischemia [13] but ischemia-reperfusion injury determines
final infarct size [14] which possibly explains these observations. Also, in these patients there might have been previous arterial narrowings, leading to outgrowth of the collateral circulation before onset of the infarct. Not only between, but actually also within species, a large variance is observed. In the previously mentioned study by Eckstein et al. [9], a large variability was found in functional and anatomic intercoronary arterial anastomoses within the group of mongrel dogs. The same observation was done in mongrel dogs in a study by Bishop where they noted a remarkable variation in the presence of pre-existing collateral circulation as evidenced by the wide range of infarct sizes produced by proximal occlusion of a major coronary artery branch [15]. In a study specifically addressing such intra-species differences, circumflex coronary occlusions were performed in beagles and mongrels. Results showed that purebred beagles possess fewer pre-existing functional coronary collateral arteries than mongrels [16]. When comparing published data on collateral formation in other organ systems than the heart, it seems that in murine, rabbit and dog models the pre-existing collateral circulation of the hindlimb has a low capacity as compared to rat and pig models (Table 2). Precaution should be taken since different methods of measuring collateral flow were applied. Also sometimes maximal vasodilatation is applied, to correct for differences in vascular tone as a confounder, whereas in other instances only baseline flow is measured. Intraspecies differences have been well documented for the pre-existing collateral circulation in the hindlimb. Several studies consistently concluded that C57BL/6 mice have a higher number of visible preexistent collaterals compared to BALB/c mice [17].
3. Inter- and intra-species differences in the arteriogenic response Not only the pre-existent collateral network differs, also the arteriogenic response, i.e. the outgrowth of collateral arteries upon arterial obstruction, can differ enormously depending on species or strain. Extensive research has been executed to map these differences because they influence the choice of an experimental model. Pigs were not only reported to possess a weakly developed preexisting coronary collateral network as mentioned above, it was also claimed that they show hardly any arteriogenic response upon coronary occlusion. Schaper and colleagues compared chronic coronary artery occlusion in pigs and dogs, using arterial back pressure as a measure of collateral perfusion [18]. Indeed in only 11 of 25 pigs, arterial back pressure could be measured, compared to all of the 68 dogs. The supposed increased collateral capacity in dogs as compared to pigs has been contradicted by Unger [19]. In recent years several studies were performed to test the efficacy of compounds to stimulate collateral growth in pigs. In most studies, also control animals [20] displayed a clear arteriogenic response. For example, Carroll et al. assessed collateral flow at different time points after coronary
Table 1 Percentages of collateral flow after acute coronary artery occlusion as compared to baseline flow. Species
Strain
Collateral flow
Method
Guinea pig Rat Rabbit Cat Pig Dog
Dunkin Hartley [2] Wistar [2, 4] New Zealand white [2, 5] Felis canus [2] Sus vitatus [2, 6] Beagle [16] Greyhound [2] Mongrel [7, 16]
100% 5% 2% 12% 1% 14% 16% 17%
Radioactive Radioactive Radioactive Radioactive Radioactive Radioactive Radioactive Radioactive
Hyperemia/resting microspheres microspheres microspheres microspheres microspheres microspheres microspheres microspheres
Resting Resting Resting Resting Resting Hyperemia Resting Hyperemia
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Table 2 Percentages of collateral flow after acute femoral artery occlusion as compared to baseline flow. Species
Strain
Collateral flow
Method
Hyperemia/resting
Mouse
BALB/c [16] C57BL/6 [31] Sprague–Dawley [76] Sprague–Dawley [4] New Zealand White [29] Göttinger minipig [34] Minipig [77] Farmpig [77] Beagle [35]
2% 7% 27% 10% 1% 23% 9% 9% 1%
Laser Doppler perfusion imaging Laser Doppler perfusion imaging Laser Doppler perfusion imaging Fluorescent microspheres Fluorescent microspheres Flow-probe Flow-probe Flow-probe Flow-probe
Hyperemia Hyperemia Resting Resting Hyperemia Hyperemia Hyperemia Hyperemia Resting
Rat Rabbit Pig
Dog
occlusion using an ameroid constrictor and subsequent treatment with heparin. They found that in untreated control animals resting myocardial blood flow was restored to normal levels at day 28, although hyperaemic flow was still reduced [21]. An important issue is the timing of the coronary occlusion. Due to the lower capacity of the pre-existing collateral circulation, pigs show relatively large areas of myocardial infarction. Such infarcted, non-contracting tissue is in low need of oxygen and perfusion. Thus, in this situation a strong arteriogenic response would be redundant. However, Hoefer et al. showed that in very slowly progressive coronary occlusion in pigs also a relatively strong arteriogenic response is induced [22]. The porcine inability to develop coronary collaterals upon arterial obstruction can thus partially be redressed. Several studies were done to determine the suggested well endowed canine arteriogenic capacity. Using radioactive microspheres to measure collateral flow, Bishop et al. found a modest increase in the canine collateral blood flow as early as 4 days after coronary occlusion [15]. With the same technique to measure collateral flow, Mills et al. showed a normalization of myocardial blood flow 6 weeks after start of gradual occlusion [23]. Cohen reported the appearance of collaterals in canine hearts in the first weeks after coronary occlusion and a complete restoration of blood flow to the area targeted by the occlusion by 4 weeks [24]. Within mongrel dogs, significant differences were found in the response to chronic coronary stenosis. In 17 mongrels, a stenosis of the left circumflex coronary artery was created, restricting reactive hyperemia without affecting resting flow. After 5 weeks, tracer microspheres were used to assess myocardial blood flow. The documented responses were a lack of collateral growth in eleven animals but significant collateral growth in the other six dogs [25]. Besides large species mentioned above, chronic cardiac ischemia was also studied in small species like rabbits and rats. Using an ameroid constrictor, specially designed for small diameters, Operschall et al. gradually narrowed the circumflex coronary artery in New Zealand White rabbits [5]. At different time points, patency of the vessel was evaluated by coronary angiography, corrosion cast and radiolabelled microspheres. 21 days after implantation of the device, angiography showed either total occlusion or severe stenosis. Seven out of the eight corrosion casts showed a stump on the targeted vessel and one animal showed a severe stenosis. Microsphere measurements showed a significantly lower perfusion of the endocardial region than the epicardial region. Blood flow on day 21 was restored to almost normal in the epicardial layer and to about 50% in the endocardial layer, indicating a substantial arteriogenic response. The group of Chilian showed that the ameroid constrictor, in an even smaller version, was also feasible in the coronary circulation of rats. They found that vascular endothelial growth factor is necessary for coronary collateral growth in this model, showing no increase of coronary collaterals in the control group [26]. In a recent study by Carrao et al., only a modest arteriogenic capacity of the rat heart was found
[27]. The increase of collaterals was less than in the group treated with granulocyte-colony stimulating factor (G-CSF), but still enough to cause for an improvement in ejection fraction in one fourth of the non-treated group. Ponies also show a clear ischemia induced arteriogenic response. Repeated occlusion of the left anterior descending coronary artery in ponies led to enhanced coronary collateral flow such that left ventricular function was maintained in absence of left anterior descending coronary artery flow [28]. Upon femoral artery ligation rats and mice restore perfusion very fast whereas rabbits seem to have a very low arteriogenic response as compared to other species [29–31]. Also pigs show a strong arteriogenic response in the hindlimb [32–34] whereas in the dog model it seems to be relatively modest [35]. This implies that extrapolation from hindlimb arteriogenic models to coronary arteriogenic models should be done with precaution. Findings from hindlimb models have to be verified in coronary models before drawing conclusions on coronary collateral stimulation or proceeding down the line to clinical trials. Also important to note is that differences can be detected in the quantity of collateral vessels but also in the morphological composition of the collateral network. Microvascular networks in C57BL/6 mice demonstrated remodelling at the arteriolar level whereas BALB/c displayed diameter expansion mainly in the capillaries [31].
4. Differences in the pre-existing collateral network and the arteriogenic response in patients It was demonstrated decades ago by Fulton [36] that also the human heart contains a large pre-existent collateral network already before the onset of obstructive atherosclerotic disease. His compelling angiographic data settled the ongoing debate on whether or not such a pre-existing collateral network is present at all in humans. In his studies he observed a remarkable variety in number and diameter of the collateral vessels and already suspected a genetically determined variation. More recently, these angiographic data were confirmed by intracoronary measurements of collateral flow. Collateral flow index (CFI) measurements of the coronary arteries in 100 patients without stenotic lesions were performed to investigate whether pre-existing collaterals show functional collateral flow in individuals with angiographically normal coronary arteries [37]. Results showed that one fifth of individuals have immediately recruitable collateral flow, sufficient to prevent myocardial ischemia in case of brief coronary occlusion. Thus, also using intracoronary measurements of collateral flow, a pre-existing collateral circulation can be detected and not only the angiographic appearance but also the capacity of this pre-existing network varies largely in humans. Such variation has also been observed in the pre-existing cerebral and peripheral collateral circulation [38-40]. It is further corroborated by the observation that acute trauma to the leg arterial circulation in soldiers from World War II led to acute ischemia and leg amputation in some and to almost no flow deficit in others [41]. Thus, in humans
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Fig. 1. Distribution of CFI in patients with 0, 1, 2 or 3 vessel obstruction [45].
a large innate variance exists in the pre-existing collateral network in several organ systems. The most important determinant for the arteriogenic response in patients is the severity of the underlying arterial obstruction [42]. However, the correlation is relatively weak and within the same grade of arterial stenosis large inter-individual differences in the arteriogenic response have been documented. Pijls et al. measured CFI in 120 patients undergoing elective coronary angioplasty [43]. In their study, in 90 of 120 patients, ischemia was present at balloon inflation. Pohl et al. determined the extent of the collateral circulation in 450 patients with coronary artery disease [44]. They found that about two-thirds of the patients do not have enough collateral flow to prevent myocardial ischemia during coronary occlusion. In a large cohort study with over 800 patients, Meier also found that about two-thirds of patients have an under-developed collateral circulation which was associated with a higher cardiovascular mortality at 10 years follow-up [45]. They found Gaussian-like distributions of the extent of the collateral circulation, pointing again at innate differences. A modest shift to the right is observed when comparing the median CFI of patients with either single-, dual- or triple coronary artery disease to patients without
Frequency distribution (%)
35 CAD patients with CTO n= 97 Median CFI: 0.356
30 25 20 15 10 5 0 0-.1
.1-.2
.2-.3
.3-.4 .4-.5 .5-.6 .6-.7 Collateral flow index, CFI
.7-.8
.8-.9
.9-1
Fig. 2. Distribution of CFI in CAD patients with coronary total occlusion (CTO).
significant stenoses (Fig. 1). Only in patients with chronic total occlusion of a coronary artery, a strong shift to the right is observed, but again with large inter-individual differences. (Fig. 2, combined data from Prof. C. Seiler and our own database.) 5. Non-genetic determinants of coronary collateral flow Several environmental risk factors potentially influence the arteriogenic response in patients. Evidence for such relations has been provided by dedicated experimental disease models as well as by observations in patients (see Table 3). 5.1. Dyslipidemia Arteriogenesis is hampered in case of hypercholesterolemia as shown in rabbits and pigs. Using fluorescent microspheres, this delayed arteriogenic response was noticed in a rabbit model [46] of hypercholesterolemia, when compared to historic controls. In pigs, fed with a cholesterol-rich diet, the collateral response upon slowly progressive coronary artery obstruction was also delayed [47]. In patients, dyslipidemia was reported to be positively associated with spontaneously visible collateral arteries. This is probably related to more severe coronary artery disease [48]. 5.2. Hyperglycemia Hyperglycemia leads to changes in endothelial function, vascular smooth muscle cell proliferation and the interaction between vessel wall and circulating cells [49]. These processes are important in collateral artery formation and thus an effect of hyperglycemia appears conceivable. In one study, patients with diabetes developed less angiographically visible coronary collateral vessels than non-diabetic control patients [50]. However, a study using more accurate and quantitative CFI measurements in 100 diabetic patients and 100 non-diabetic patients contradicted this, revealing no difference in collateral function between the groups [51].
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Table 3 Non-genetic determinants of coronary collateral formation.
Dyslipidemia Hyperglycemia Hypertension Obesity Smoking Inflammation Aging
Experimental models
Patient studies
Inhibited collateral growth [47,46] Inhibited collateral growth [49] Promoted collateral growth [78] No direct evidence [53] Promoted collateral growth [79] Promoted collateral growth [56] Inhibited collateral growth [65,77,80,81]
No direct evidence Inhibited collateral growth [50]/no difference [51] Inhibited collateral growth [52] Inhibited collateral growth [53]/no direct evidence Promoted collateral growth [55]/no direct evidence Promoted collateral growth/inhibited collateral growth [62–64] Inhibited collateral growth [66, 67]
5.3. Hypertension
5.7. Aging
Evidence on the connection between collateral growth and hypertension is scarce. A high blood pressure increases shear stress. As shear stress is a main driving force of arteriogenesis, one hypothesis is that hypertension promotes collateral growth. However, hypertension is also associated with vascular dysfunction, likely reducing arterial remodelling and inhibiting collateral artery growth. In patients an inverse relation was found between high blood pressure and the extent of coronary collaterals in a cross-sectional study in 237 patients [52].
In a comparing study between C57BL/6 mice of 6 to 8 months and 22 to 24 months, left anterior descending coronary artery ligation was performed. The hearts were reperfused after 45 min whereupon the hearts were examined. A significant difference was found between infarct size in the young and old mice where the old mice showed larger infarcted areas [65]. In a study in 102 patients with an acutely occluded coronary artery, the extent of collateral development was determined. The patient group was divided into a ‘young’ and an ‘old’ group, and between the groups a significant difference was found with a higher prevalence of a well developed collateral circulation in the younger group [66]. In a cohort of 1934 patients with acute myocardial infarction, aging was recognized as being a factor predicting the number of collaterals present when vascular occlusion happens. The prevalence of collaterals decreased with age [67]. Taken together, both experimental data as well as clinical observations point to an important role for age in the arteriogenic response.
5.4. Obesity There are limited data regarding the link between obesity and arteriogenesis. Yilmaz et al. found a poorer coronary collateral circulation in obese patients with ischemic heart disease compared with patients not suffering from obesity [53]. Confounders in these findings may well be altered lipid profiles and insulin resistance which are often present in obese patients. Dyslipidemia, hyperglycemia, hypertension and obesity are components of the metabolic syndrome. Turhan et al. [54] concluded that patients with metabolic syndrome have impaired coronary collateral vessel development. No association was found between the presence of metabolic syndrome in 103 of 227 patients with coronary artery disease and formation of collateral vessels on angiography. 5.5. Smoking Clinical studies do not show a consistent relation between collateralization and smoking although one study found a positive association with the presence of collateral arteries on angiography [55]. The amount of pack years did not contribute, only current smoking status did. 5.6. Inflammation Arteriogenesis resembles inflammatory disease in many ways. The role of monocytes in arteriogenesis is well established [56, 57]. Also other immune cells like T-cells and natural killer-cells play an important role [58]. Treatment with pro-inflammatory compounds like lipopolysaccharide or tumor necrosis factor-alpha agonists enhances collateral artery growth [59]. When studying the role of monocyte chemotactic protein-1 (MCP-1) in acute myocardial infarction, plasma MCP-1 levels in patients were significantly higher in a group with well developed collaterals compared to a group with absent collateral circulation [60]. Interestingly, coronary collateral flow was associated with higher alpha-1-acid glycoprotein and C-reactive protein concentrations [61]. This underlines the role of acute phase proteins in collateral development. However, the finding on CRP was contradicted by several other studies, reporting that elevated CRP levels are associated with impairment of coronary collateralization [62-64].
6. Genetic determinants of collateral flow During the last years several efforts were made in both experimental as well as clinical studies to identify genetic factors that determine the arteriogenic response upon arterial obstruction. 6.1. Experimental models Several of the observations on genetic determinants of collateral artery growth are derived from experimental models of hindlimb ischemia. Lee et al. [68] extracted ribonucleic acid from adductor muscle in mice and used array expression profiling to determine the time course of differential expression of 12,000 genes after ligation of the femoral artery in C57BL/6 mice. Between the femoral artery ligation group and the sham group, 783 genes showed a differential expression where 518 were induced and 265 were repressed. Interestingly, a number of angiogenesis-related genes such as MCP1, placental growth factor and cysteine-rich protein-61, were differentially upregulated in the femoral artery ligation group as compared to the sham group. Also, a significant upregulation was found in genes thought to exert angiostatic activities, including interferon-gammainducible protein-10, monokine induced by interferon gamma and matrix metalloproteinase-12 in the ligated group. Of the different gene clusters, the inflammatory response-related genes cluster was the largest that was upregulated. Even though they were upregulated in both groups, the genes showed higher expression levels with longer duration in the femoral artery ligation versus the sham group. Wang et al. [3] executed a study to identify possible loci responsible for the variation in the arteriogenic response. In C57BL/6 × BALB/c F2 mice, cerebral collateral number and diameter were measured. After this, linkage analysis was carried out to identify quantitative trait loci (QTL) for collateral number and diameter. Collateral number and diameter were minimally correlated, consistent with Zhang et al. [69]
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and indicating that number and diameter are mainly independent traits. With genome wide logarithm of odds score profiling a highly significant locus on distal chromosome 7 was found for the collateral traits collateral number and collateral diameter. To confirm the major effect of chromosome 7, chromosome substitution was executed on A/J mice strain, which showed fewer pial collaterals than C57BL/6 mice and also a substantially smaller diameter. 6.2. Patients CD44 glycoproteins have a function as a receptor for leukocytes [70] as well as in the regulation of growth factor activation. In wild-type C57BL/6J mice, the expression of CD44 was found to be strongly increased in collateral arteries in the hind limb muscles [71]. CD44−/− mice showed a strong reduction in the arteriogenic response upon femoral artery ligation in comparison to the wildtype mice. Next, CD44 expression in patients was studied. In patients with a poor collateralization, CD44 expression was significantly decreased. These data showed that indeed expression differences can be detected between patients with either a poor or a well developed collateral circulation. This led to the design of a large RNA expression analysis study in patients. In a first cohort of 50 patients, CFI was measured and the group was divided into collateral responders and nonresponders. Blood samples were taken and genome-wide mRNA expression analysis was performed on monocytes. 244 differentially expressed genes were identified in stimulated monocytes. In the group of nonresponders, interferon-beta (IFN-beta) and other IFN-related genes demonstrated increased mRNA levels, linking IFN-beta to a hampered arteriogenic response. To validate the resulting hypothesis that IFN-beta attenuates arteriogenesis, perfusion was measured in a murine hindlimb model after ligation of the femoral artery. Significantly reduced arteriogenesis was displayed in mice treated with IFN-beta compared to controls. Furthermore, IFN-beta-receptor-1 knockout mice showed significantly better restoration of perfusion in the hindlimb 1 week after ligation compared to control mice in another study using microspheres. Finally, in an independent cohort of 50 patients with coronary total occlusion, again IFN-beta was strongly enriched in gene expression analysis [72]. At the same time Meier et al. performed a whole genome-analysis, using a larger population and also including subjects without coronary artery disease. They found differential expression of 203 genes which were involved in integrin, platelet-derived growth factor and transforming growth factor beta-signalling [73]. In a cohort of 226 patients (84 with and 142 without visible collaterals) nine single nucleotide polymorphisms (SNPs) were identified which potentially have effects on collateral formation [74]. These SNPs reflected genes involved in inflammation. Another factor that was recently distilled from patient data and experimentally validated is galectin-2. This factor is also overexpressed in patients with poor collateral arteries and exogenous application of this factor leads to a strong reduction in the arteriogenic response in the murine hindlimb model [75]. 7. Discussion The large variation between and within species in both the preexisting coronary collateral circulation as well as the arteriogenic response upon arterial occlusion strongly suggests that innate genetic factors are at stake, besides environmental factors. These differences can have strong implications for the choice of an experimental model. For example, when trying to induce collateral artery growth it is more appropriate to use a model of a relatively low innate arteriogenic response since otherwise it will be difficult to supersede this with a pharmacological compound. In more mechanistic studies,
when searching for factors that hamper collateral arteriogenesis, the opposite is true. Which model best mimics the clinical situation is difficult to tell since patients are very heterogenic, sometimes approaching pigs and sometimes coming closer to dogs regarding the collateral circulation. Interestingly, properties of the collateral circulation are consistent within different organ systems. That is, if the arteriogenic response is low in the coronary circulation, it is also low in the peripheral or the cerebral circulation. This notion is of clinical importance, although validation from patient databases (for example showing an association between cerebral and myocardial infarct size) are to the best of our knowledge not available. Also interesting is the fact that the capacity of the pre-existing collateral network does not always seem to relate to the arteriogenic response. Thus, different innate factors seem to be at stake for these two processes. Another important message is that not only the rate of proliferation determines the final capacity of the collateral circulation but also the morphological characteristics (large calibre capillaries versus true arterial connections) of the vasculature. Thus, it is not only a matter of quantity but also of quality. Recently, state-of-the art genomic and proteomic technologies identified several candidate genes responsible for the arteriogenic heterogeneity in patients. Given the complex multigenetic and lifestyle confounded nature of arteriogenesis, such genome wide technologies, combined with systems biology expectedly will propel the arteriogenic field into a new era of progress towards clinical application. Disclosures None. Acknowledgment We would like to thank Prof. Dr. C. Seiler for providing data on CFImeasurements in patients with a chronic total occlusion. References [1] Schaper W. Collateral circulation: past and present. Basic Res Cardiol 2009;104: 5–21. [2] Maxwell MP, Hearse DJ, Yellon DM. 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: 737–46. [3] Wang S, Zhang H, Dai X, Sealock R, Faber JE. Genetic architecture underlying variation in extent and remodeling of the collateral circulation. Circ Res 2010;107: 558–68. [4] Hale SL, Kloner RA. Effect of early coronary artery reperfusion on infarct development in a model of low collateral flow. Cardiovasc Res 1987;21:668–73. [5] Operschall C, Falivene L, Clozel JP, Roux S. A new model of chronic cardiac ischemia in rabbits. J Appl Physiol 2000;88:1438–45. [6] White FC, Carroll SM, Magnet A, Bloor CM. Coronary collateral development in swine after coronary artery occlusion. Circ Res 1992;71:1490–500. [7] Schaper W, Flameng W, Winkler B, Wusten B, Turschmann W, Neugebauer G, et al. Quantification of collateral resistance in acute and chronic experimental coronary occlusion in the dog. Circ Res 1976;39:371–7. [8] Heusch G, Skyschally A, Schulz R. The in-situ pig heart with regional ischemia/ reperfusion – ready for translation. J Mol Cell Cardiol 2011;50:951–63. [9] Eckstein RW. Coronary interarterial anastomoses in young pigs and mongrel dogs. Circ Res 1954;2:460–5. [10] Sjoquist PO, Duker G, Almgren O. Distribution of the collateral blood flow at the lateral border of the ischemic myocardium after acute coronary occlusion in the pig and the dog. Basic Res Cardiol 1984;79:164–75. [11] McDonough KH, Dunn RB, Griggs Jr DM. Transmural changes in porcine and canine hearts after circumflex artery occlusion. Am J Physiol 1984;246:H601–7. [12] Patterson RE, Kirk ES. Analysis of coronary collateral structure, function, and ischemic border zones in pigs. Am J Physiol 1983;244:H23–31. [13] Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S. An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. N Engl J Med 1992;327:1825–31. [14] Hedstrom E, Engblom H, Frogner F, Astrom-Olsson K, Ohlin H, Jovinge S, et al. Infarct evolution in man studied in patients with first-time coronary occlusion in comparison to different species – implications for assessment of myocardial salvage. J Cardiovasc Magn Reson 2009;11:38.
P.F.A. Teunissen et al. / Journal of Molecular and Cellular Cardiology 52 (2011) 897–904 [15] Bishop SP, White FC, Bloor CM. Regional myocardial blood flow during acute myocardial infarction in the conscious dog. Circ Res 1976;38:429–38. [16] Uemura N, Knight DR, Shen YT, Nejima J, Cohen MV, Thomas Jr JX, et al. Increased myocardial infarct size because of reduced coronary collateral blood flow in beagles. Am J Physiol 1989;257:H1798–803. [17] Chalothorn D, Faber JE. Strain-dependent variation in collateral circulatory function in mouse hindlimb. Physiol Genomics 2010;42:469–79. [18] Schaper W, Jageneau A, Xhonneux R. The development of collateral circulation in the pig and dog heart. Cardiologia 1967;51:321–35. [19] Unger EF. Experimental evaluation of coronary collateral development. Cardiovasc Res 2001;49:497–506. [20] Sato K, Laham RJ, Pearlman JD, Novicki D, Sellke FW, Simons M, et al. Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia. Ann Thorac Surg 2000;70:2113–8. [21] Carroll SM, White FC, Roth DM, Bloor CM. Heparin accelerates coronary collateral development in a porcine model of coronary artery occlusion. Circulation 1993;88: 198–207. [22] de Groot D, Grundmann S, Timmers L, Pasterkamp G, Hoefer IE. Assessment of collateral artery function and growth in a pig model of stepwise coronary occlusion. Am J Physiol Heart Circ Physiol 2011;300:H408–14. [23] Mills JD, Fischer D, Villanueva FS. Coronary collateral development during chronic ischemia: serial assessment using harmonic myocardial contrast echocardiography. J Am Coll Cardiol 2000;36:618–24. [24] 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. [25] Schwarz F, Wagner HO, Sesto M, Hofmann M, Schaper W, Kubler W. Native collaterals in the development of collateral circulation after chronic coronary stenosis in mongrel dogs. Circulation 1982;66:303–8. [26] Toyota E, Warltier DC, Brock T, Ritman E, Kolz C, O'Malley P, et al. Vascular endothelial growth factor is required for coronary collateral growth in the rat. Circulation 2005;112:2108–13. [27] Carrao AC, Chilian WM, Yun J, Kolz C, Rocic P, Lehmann K, et al. Stimulation of coronary collateral growth by granulocyte stimulating factor: role of reactive oxygen species. Arterioscler Thromb Vasc Biol 2009;29:1817–22. [28] Rugh KS, Garner HE, Hatfield DG, Miramonti JR. Ischaemia induced development of functional coronary collateral circulation in ponies. Cardiovasc Res 1987;21: 730–6. [29] Hoefer IE, van R N, Buschmann IR, Piek JJ, Schaper W. Time course of arteriogenesis following femoral artery occlusion in the rabbit. Cardiovasc Res 2001;49: 609–17. [30] Sheridan KM, Ferguson MJ, Distasi MR, Witzmann FA, Dalsing MC, Miller SJ, et al. Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 × Brown Norway hybrid rats. Am J Physiol Heart Circ Physiol 2007;293:H3498–505. [31] MacGabhann F, Peirce SM. Collateral capillary arterialization following arteriolar ligation in murine skeletal muscle. Microcirculation 2010;17:333–47. [32] Troidl C, Nef H, Voss S, Schilp A, Kostin S, Troidl K, et al. Calcium-dependent signalling is essential during collateral growth in the pig hind limb-ischemia model. J Mol Cell Cardiol 2010;49:142–51. [33] Pipp F, Boehm S, Cai WJ, Adili F, Ziegler B, Karanovic G, et al. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb. Arterioscler Thromb Vasc Biol 2004;24:1664–8. [34] Voskuil M, van R N, Hoefer IE, Seidler R, Guth BD, Bode C, et al. Modulation of collateral artery growth in a porcine hindlimb ligation model using MCP-1. Am J Physiol Heart Circ Physiol 2003;284:H1422–8. [35] Rakue H, Nakajima H, Katoh T, Usui M, Amemiya T, Miyagi M, et al. Low-dose basic fibroblast growth factor and vascular endothelial growth factor for angiogenesis in canine acute hindlimb insufficiency. Jpn Circ J 1998;62:933–9. [36] Fulton WF. Arterial anastomoses in the coronary circulation. II. Distribution, enumeration and measurement of coronary arterial anastomoses in health and disease. Scott Med J 1963;8:466–74. [37] Wustmann K, Zbinden S, Windecker S, Meier B, Seiler C. Is there functional collateral flow during vascular occlusion in angiographically normal coronary arteries? Circulation 2003;107:2213–20. [38] Bang OY, Saver JL, Buck BH, Alger JR, Starkman S, Ovbiagele B, et al. Impact of collateral flow on tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychiatry 2008;79:625–9. [39] Maas MB, Lev MH, Ay H, Singhal AB, Greer DM, Smith WS, et al. Collateral vessels on CT angiography predict outcome in acute ischemic stroke. Stroke 2009;40: 3001–5. [40] Abul-Khoudoud O. Diagnosis and risk assessment of lower extremity peripheral arterial disease. J Endovasc Ther 2006;13(Suppl 2):II10–8. [41] DeBakey ME, Simeone FA. Battle Injuries of the Arteries in World War II : An Analysis of 2,471 Cases. Ann Surg 1946;123:534–79. [42] Pohl T, Seiler C, Billinger M, Herren E, Wustmann K, Mehta H, et al. Frequency distribution of collateral flow and factors influencing collateral channel development. Functional collateral channel measurement in 450 patients with coronary artery disease. J Am Coll Cardiol 2001;38:1872–8. [43] Pijls NH, Bech GJ, el Gamal MI, Bonnier HJ, De BB, Van GB, et al. Quantification of recruitable coronary collateral blood flow in conscious humans and its potential to predict future ischemic events. J Am Coll Cardiol 1995;25: 1522–8. [44] Pohl T, Hochstrasser P, Billinger M, Fleisch M, Meier B, Seiler C. Influence on collateral flow of recanalising chronic total coronary occlusions: a case-control study. Heart 2001;86:438–43.
903
[45] Meier P, Gloekler S, Zbinden R, Beckh S, de Marchi SF, Zbinden S, et al. Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements. Circulation 2007;116:975–83. [46] van Royen N, Hoefer I, Buschmann I, Kostin S, Voskuil M, Bode C, et al. Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits. Cardiovasc Res 2003;57:178–85. [47] Boodhwani M, Nakai Y, Mieno S, Voisine P, Bianchi C, Araujo EG, et al. Hypercholesterolemia impairs the myocardial angiogenic response in a swine model of chronic ischemia: role of endostatin and oxidative stress. Ann Thorac Surg 2006;81: 634–41. [48] Kornowski R. Collateral formation and clinical variables in obstructive coronary artery disease: the influence of hypercholesterolemia and diabetes mellitus. Coron Artery Dis 2003;14:61–4. [49] Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation 2002;106:3037–43. [50] Abaci A, Oguzhan A, Kahraman S, Eryol NK, Unal S, Arinc H, et al. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 1999;99:2239–42. [51] Zbinden R, Zbinden S, Billinger M, Windecker S, Meier B, Seiler C. Influence of diabetes mellitus on coronary collateral flow: an answer to an old controversy. Heart 2005;91:1289–93. [52] Koerselman J, de Jaegere PP, Verhaar MC, van der Graaf Y, Grobbee DE. High blood pressure is inversely related with the presence and extent of coronary collaterals. J Hum Hypertens 2005;19:809–17. [53] Yilmaz MB, Biyikoglu SF, Akin Y, Guray U, Kisacik HL, Korkmaz S. Obesity is associated with impaired coronary collateral vessel development. Disord 2003;27: 1541–5. [54] Turhan H, Yasar AS, Erbay AR, Yetkin E, Sasmaz H, Sabah I. Impaired coronary collateral vessel development in patients with metabolic syndrome. Coron Artery Dis 2005;16:281–5. [55] Koerselman J, de Jaegere PP, Verhaar MC, Grobbee DE, van der Graaf Y. Coronary collateral circulation: the effects of smoking and alcohol. Atherosclerosis 2007;191: 191–8. [56] Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998;101: 40–50. [57] Heil M, Ziegelhoeffer T, Pipp F, Kostin S, Martin S, Clauss M, et al. Blood monocyte concentration is critical for enhancement of collateral artery growth. Am J Physiol Heart Circ Physiol 2002;283:H2411–9. [58] van W V, Toes RE, Seghers L, Deckers MM, de Vries MR, Eilers PH, et al. Natural killer cells and CD4+ T-cells modulate collateral artery development. Arterioscler Thromb Vasc Biol 2007;27:2310–8. [59] Grundmann S, Hoefer I, Ulusans S, van R N, Schirmer SH, Ozaki CK, et al. Antitumor necrosis factor-{alpha} therapies attenuate adaptive arteriogenesis in the rabbit. Am J Physiol Heart Circ Physiol 2005;289:H1497–505. [60] Park HJ, Chang K, Park CS, Jang SW, Ihm SH, Kim PJ, et al. Coronary collaterals: the role of MCP-1 during the early phase of acute myocardial infarction. Int J Cardiol 2008;130:409–13. [61] Brunetti ND, Correale M, Pellegrino PL, Cuculo A, Biase MD. Acute phase proteins in patients with acute coronary syndrome: correlations with diagnosis, clinical features, and angiographic findings. Eur J Intern Med 2007;18:109–17. [62] Gulec S, Ozdemir AO, Maradit-Kremers H, Dincer I, Atmaca Y, Erol C. Elevated levels of C-reactive protein are associated with impaired coronary collateral development. Eur J Clin Invest 2006;36:369–75. [63] Solorio S, Murillo-Ortiz B, Hernandez-Gonzalez M, Guillen-Contreras J, Arenas-Aranda D, Solorzano-Zepeda FJ, et al. Association Between Telomere Length and c-Reactive Protein and the Development of Coronary Collateral Circulation in Patients With Coronary Artery Disease. Angiology 2011 Aug;62(6):467–73. [64] Kerner A, Gruberg L, Goldberg A, Roguin A, Lavie P, Lavie L, et al. Relation of C-reactive protein to coronary collaterals in patients with stable angina pectoris and coronary artery disease. Am J Cardiol 2007;99:509–12. [65] Azhar G, Gao W, Liu L, Wei JY. Ischemia-reperfusion in the adult mouse heart influence of age. Exp Gerontol 1999;34:699–714. [66] Nakae I, Fujita M, Miwa K, Hasegawa K, Kihara Y, Nohara R, et al. Age-dependent impairment of coronary collateral development in humans. Heart Vessels 2000;15: 176–80. [67] Kurotobi T, Sato H, Kinjo K, Nakatani D, Mizuno H, Shimizu M, et al. Reduced collateral circulation to the infarct-related artery in elderly patients with acute myocardial infarction. J Am Coll Cardiol 2004;44:28–34. [68] Lee CW, Stabile E, Kinnaird T, Shou M, Devaney JM, Epstein SE, et al. Temporal patterns of gene expression after acute hindlimb ischemia in mice: insights into the genomic program for collateral vessel development. J Am Coll Cardiol 2004;43: 474–82. [69] Zhang H, Prabhakar P, Sealock R, Faber JE. Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cereb Blood Flow Metab 2010;30:923–34. [70] DeGrendele HC, Estess P, Siegelman MH. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 1997;278:672–5. [71] van R N, Voskuil M, Hoefer I, Jost M, de G S, Hedwig F, et al. CD44 regulates arteriogenesis in mice and is differentially expressed in patients with poor and good collateralization. Circulation 2004;109:1647–52. [72] Schirmer SH, Fledderus JO, Bot PT, Moerland PD, Hoefer IE, Baan Jr J, et al. Interferonbeta signaling is enhanced in patients with insufficient coronary collateral artery development and inhibits arteriogenesis in mice. Circ Res 2008;102:1286–94.
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P.F.A. Teunissen et al. / Journal of Molecular and Cellular Cardiology 52 (2011) 897–904
[73] Meier P, Antonov J, Zbinden R, Kuhn A, Zbinden S, Gloekler S, et al. Non-invasive gene-expression-based detection of well-developed collateral function in individuals with and without coronary artery disease. Heart 2009;95: 900–8. [74] Zhang J, Regieli JJ, Schipper M, Entius MM, Liang F, Koerselman J, et al. Inflammatory gene haplotype-interaction networks involved in coronary collateral formation. Hum Hered 2008;66:252–64. [75] van der Laan AM, Schirmer SH, de Vries MR, Koning JJ, Volger OL, Fledderus JO, et al. Galectin-2 expression is dependent on the rs7291467 polymorphism and acts as an inhibitor of arteriogenesis. Eur Heart J in press. doi:10.1093/eurheartj/ ehr220. Epub ahead of print. [76] Tang GL, Chang DS, Sarkar R, Wang R, Messina LM. The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia. J Vasc Surg 2005;41:312–20.
[77] Buschmann IR, Voskuil M, van R N, Hoefer IE, Scheffler K, Grundmann S, et al. Invasive and non-invasive evaluation of spontaneous arteriogenesis in a novel porcine model for peripheral arterial obstructive disease. Atherosclerosis 2003;167: 33–43. [78] Coyle P, Jokelainen PT. Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) and Wistar Kyoto (WKY) rats. Stroke 1983;14:605–11. [79] Heeschen C, Weis M, Cooke JP. Nicotine promotes arteriogenesis. J Am Coll Cardiol 2003;41:489–96. [80] Faber JE, Zhang H, Lassance-Soares RM, Prabhakar P, Najafi AH, Burnett MS, et al. Aging causes collateral rarefaction and increased severity of ischemic injury in multiple tissues. Arterioscler Thromb Vasc Biol 2011;31:1748–56. [81] Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, et al. Age-dependent impairment of angiogenesis. Circulation 1999;99:111–20.
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Review article
The coronary collateral circulation: Genetic and environmental determinants in experimental models and humans Paul F.A. Teunissen a, Anton J.G. Horrevoets b, Niels van Royen a,⁎ a b
Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 22 June 2011 Received in revised form 25 August 2011 Accepted 12 September 2011 Available online 19 September 2011 Keywords: Arteriogenesis Angiogenesis Collateral artery growth Genetics Coronary Collateral flow Collateral circulation Experimental Human
a b s t r a c t Obstruction of coronary arteries leads to an arteriogenic response. Pre-existent collateral networks enlarge, forming large conductance arteries with the capability to compensate for the loss of perfusion due to the occlusion. Interestingly, significant differences exist between patients regarding the capacity to develop such a collateral circulation. This heterogeneity in arteriogenic response is also found between and even within animal species and it strongly suggests that next to environmental factors, innate genetic factors play a key role. The present review focuses on this heterogeneity of genetic as well as non-genetic determinants of the coronary collateral circulation. This article is part of a Special Issue entitled “Coronary Blood Flow”. © 2011 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inter- and intra-species differences in the pre-existing collateral network . . . . . . . Inter- and intra-species differences in the arteriogenic response . . . . . . . . . . . Differences in the pre-existing collateral network and the arteriogenic response in patients Non-genetic determinants of coronary collateral flow . . . . . . . . . . . . . . . . 5.1. Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Genetic determinants of collateral flow . . . . . . . . . . . . . . . . . . . . . . . 6.1. Experimental models . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: VU University Medical Center, Department of Cardiology, Room 5F-013, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel.: + 31 20 4444460; fax: + 31 20 444 2446. E-mail address: [email protected] (N. van Royen). 0022-2828/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2011.09.010
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1. Introduction In case of coronary arterial obstruction, an arteriogenic response is induced [1], leading to an arterial collateral network which sustains blood flow to the myocardium. The development of a coronary collateral circulation is associated with better preservation of left ventricular function and lower mortality rates. However, the extent of the collateral circulation, both in healthy persons as well as in patients with obstructive coronary artery disease, varies largely. Thus, whereas in some patients severe obstructive coronary artery disease is left completely unnoticed due to a well developed collateral circulation, others seem to lack the capacity to develop a sufficient collateral network. This heterogeneity is also observed between and within different animal species. The present review focuses on this heterogeneity and genetic as well as non-genetic determinants of the coronary collateral circulation.
2. Inter- and intra-species differences in the pre-existing collateral network The pre-existing collateral network varies widely between and also within species. In the last decades several animal models were used to measure collateral flow directly upon arterial obstruction. By far the most extensive study on interspecies differences in the pre-existing coronary collateral circulation has been performed by Maxwell [2]. Baseline coronary collateral flow was compared in eight different species with radiolabelled microspheres. When representing collateral flow as a percentage of flow to the non-ischemic myocardium, a large spectrum was found. For example, rabbits and pigs show a very low capacity of about 0–6% of baseline, whereas guinea pigs display compensatory collateral flow of 100% directly after arterial obstruction. Other species like dogs have a baseline collateral flow that is somewhere in between these values. These data have been confirmed in many subsequent single species studies for mice [3], rats [4], rabbits [5], pigs [6] and dogs [7] (see Table 1). Other direct comparisons of species have been performed for porcine and canine models. From these studies it was concluded that dogs have an extensive pre-existing collateral network whereas in pigs this is almost absent, leading to transmural infarction and a large percentage of animals that do not survive acute coronary occlusion [8–12]. In a recent MRI study, infarct size and the ratio of area at risk and final infarct size were compared between different species. When comparing patient data to historical animal data they surprisingly found that evolution of infarct is slowest in humans, suggesting a pre-existing collateral protective network that is even more efficient than in dogs. However, no direct measurement of collateral flow was performed. Infarct size strongly relates to collateral flow which attenuates the severity of ischemia [13] but ischemia-reperfusion injury determines
final infarct size [14] which possibly explains these observations. Also, in these patients there might have been previous arterial narrowings, leading to outgrowth of the collateral circulation before onset of the infarct. Not only between, but actually also within species, a large variance is observed. In the previously mentioned study by Eckstein et al. [9], a large variability was found in functional and anatomic intercoronary arterial anastomoses within the group of mongrel dogs. The same observation was done in mongrel dogs in a study by Bishop where they noted a remarkable variation in the presence of pre-existing collateral circulation as evidenced by the wide range of infarct sizes produced by proximal occlusion of a major coronary artery branch [15]. In a study specifically addressing such intra-species differences, circumflex coronary occlusions were performed in beagles and mongrels. Results showed that purebred beagles possess fewer pre-existing functional coronary collateral arteries than mongrels [16]. When comparing published data on collateral formation in other organ systems than the heart, it seems that in murine, rabbit and dog models the pre-existing collateral circulation of the hindlimb has a low capacity as compared to rat and pig models (Table 2). Precaution should be taken since different methods of measuring collateral flow were applied. Also sometimes maximal vasodilatation is applied, to correct for differences in vascular tone as a confounder, whereas in other instances only baseline flow is measured. Intraspecies differences have been well documented for the pre-existing collateral circulation in the hindlimb. Several studies consistently concluded that C57BL/6 mice have a higher number of visible preexistent collaterals compared to BALB/c mice [17].
3. Inter- and intra-species differences in the arteriogenic response Not only the pre-existent collateral network differs, also the arteriogenic response, i.e. the outgrowth of collateral arteries upon arterial obstruction, can differ enormously depending on species or strain. Extensive research has been executed to map these differences because they influence the choice of an experimental model. Pigs were not only reported to possess a weakly developed preexisting coronary collateral network as mentioned above, it was also claimed that they show hardly any arteriogenic response upon coronary occlusion. Schaper and colleagues compared chronic coronary artery occlusion in pigs and dogs, using arterial back pressure as a measure of collateral perfusion [18]. Indeed in only 11 of 25 pigs, arterial back pressure could be measured, compared to all of the 68 dogs. The supposed increased collateral capacity in dogs as compared to pigs has been contradicted by Unger [19]. In recent years several studies were performed to test the efficacy of compounds to stimulate collateral growth in pigs. In most studies, also control animals [20] displayed a clear arteriogenic response. For example, Carroll et al. assessed collateral flow at different time points after coronary
Table 1 Percentages of collateral flow after acute coronary artery occlusion as compared to baseline flow. Species
Strain
Collateral flow
Method
Guinea pig Rat Rabbit Cat Pig Dog
Dunkin Hartley [2] Wistar [2, 4] New Zealand white [2, 5] Felis canus [2] Sus vitatus [2, 6] Beagle [16] Greyhound [2] Mongrel [7, 16]
100% 5% 2% 12% 1% 14% 16% 17%
Radioactive Radioactive Radioactive Radioactive Radioactive Radioactive Radioactive Radioactive
Hyperemia/resting microspheres microspheres microspheres microspheres microspheres microspheres microspheres microspheres
Resting Resting Resting Resting Resting Hyperemia Resting Hyperemia
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899
Table 2 Percentages of collateral flow after acute femoral artery occlusion as compared to baseline flow. Species
Strain
Collateral flow
Method
Hyperemia/resting
Mouse
BALB/c [16] C57BL/6 [31] Sprague–Dawley [76] Sprague–Dawley [4] New Zealand White [29] Göttinger minipig [34] Minipig [77] Farmpig [77] Beagle [35]
2% 7% 27% 10% 1% 23% 9% 9% 1%
Laser Doppler perfusion imaging Laser Doppler perfusion imaging Laser Doppler perfusion imaging Fluorescent microspheres Fluorescent microspheres Flow-probe Flow-probe Flow-probe Flow-probe
Hyperemia Hyperemia Resting Resting Hyperemia Hyperemia Hyperemia Hyperemia Resting
Rat Rabbit Pig
Dog
occlusion using an ameroid constrictor and subsequent treatment with heparin. They found that in untreated control animals resting myocardial blood flow was restored to normal levels at day 28, although hyperaemic flow was still reduced [21]. An important issue is the timing of the coronary occlusion. Due to the lower capacity of the pre-existing collateral circulation, pigs show relatively large areas of myocardial infarction. Such infarcted, non-contracting tissue is in low need of oxygen and perfusion. Thus, in this situation a strong arteriogenic response would be redundant. However, Hoefer et al. showed that in very slowly progressive coronary occlusion in pigs also a relatively strong arteriogenic response is induced [22]. The porcine inability to develop coronary collaterals upon arterial obstruction can thus partially be redressed. Several studies were done to determine the suggested well endowed canine arteriogenic capacity. Using radioactive microspheres to measure collateral flow, Bishop et al. found a modest increase in the canine collateral blood flow as early as 4 days after coronary occlusion [15]. With the same technique to measure collateral flow, Mills et al. showed a normalization of myocardial blood flow 6 weeks after start of gradual occlusion [23]. Cohen reported the appearance of collaterals in canine hearts in the first weeks after coronary occlusion and a complete restoration of blood flow to the area targeted by the occlusion by 4 weeks [24]. Within mongrel dogs, significant differences were found in the response to chronic coronary stenosis. In 17 mongrels, a stenosis of the left circumflex coronary artery was created, restricting reactive hyperemia without affecting resting flow. After 5 weeks, tracer microspheres were used to assess myocardial blood flow. The documented responses were a lack of collateral growth in eleven animals but significant collateral growth in the other six dogs [25]. Besides large species mentioned above, chronic cardiac ischemia was also studied in small species like rabbits and rats. Using an ameroid constrictor, specially designed for small diameters, Operschall et al. gradually narrowed the circumflex coronary artery in New Zealand White rabbits [5]. At different time points, patency of the vessel was evaluated by coronary angiography, corrosion cast and radiolabelled microspheres. 21 days after implantation of the device, angiography showed either total occlusion or severe stenosis. Seven out of the eight corrosion casts showed a stump on the targeted vessel and one animal showed a severe stenosis. Microsphere measurements showed a significantly lower perfusion of the endocardial region than the epicardial region. Blood flow on day 21 was restored to almost normal in the epicardial layer and to about 50% in the endocardial layer, indicating a substantial arteriogenic response. The group of Chilian showed that the ameroid constrictor, in an even smaller version, was also feasible in the coronary circulation of rats. They found that vascular endothelial growth factor is necessary for coronary collateral growth in this model, showing no increase of coronary collaterals in the control group [26]. In a recent study by Carrao et al., only a modest arteriogenic capacity of the rat heart was found
[27]. The increase of collaterals was less than in the group treated with granulocyte-colony stimulating factor (G-CSF), but still enough to cause for an improvement in ejection fraction in one fourth of the non-treated group. Ponies also show a clear ischemia induced arteriogenic response. Repeated occlusion of the left anterior descending coronary artery in ponies led to enhanced coronary collateral flow such that left ventricular function was maintained in absence of left anterior descending coronary artery flow [28]. Upon femoral artery ligation rats and mice restore perfusion very fast whereas rabbits seem to have a very low arteriogenic response as compared to other species [29–31]. Also pigs show a strong arteriogenic response in the hindlimb [32–34] whereas in the dog model it seems to be relatively modest [35]. This implies that extrapolation from hindlimb arteriogenic models to coronary arteriogenic models should be done with precaution. Findings from hindlimb models have to be verified in coronary models before drawing conclusions on coronary collateral stimulation or proceeding down the line to clinical trials. Also important to note is that differences can be detected in the quantity of collateral vessels but also in the morphological composition of the collateral network. Microvascular networks in C57BL/6 mice demonstrated remodelling at the arteriolar level whereas BALB/c displayed diameter expansion mainly in the capillaries [31].
4. Differences in the pre-existing collateral network and the arteriogenic response in patients It was demonstrated decades ago by Fulton [36] that also the human heart contains a large pre-existent collateral network already before the onset of obstructive atherosclerotic disease. His compelling angiographic data settled the ongoing debate on whether or not such a pre-existing collateral network is present at all in humans. In his studies he observed a remarkable variety in number and diameter of the collateral vessels and already suspected a genetically determined variation. More recently, these angiographic data were confirmed by intracoronary measurements of collateral flow. Collateral flow index (CFI) measurements of the coronary arteries in 100 patients without stenotic lesions were performed to investigate whether pre-existing collaterals show functional collateral flow in individuals with angiographically normal coronary arteries [37]. Results showed that one fifth of individuals have immediately recruitable collateral flow, sufficient to prevent myocardial ischemia in case of brief coronary occlusion. Thus, also using intracoronary measurements of collateral flow, a pre-existing collateral circulation can be detected and not only the angiographic appearance but also the capacity of this pre-existing network varies largely in humans. Such variation has also been observed in the pre-existing cerebral and peripheral collateral circulation [38-40]. It is further corroborated by the observation that acute trauma to the leg arterial circulation in soldiers from World War II led to acute ischemia and leg amputation in some and to almost no flow deficit in others [41]. Thus, in humans
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Fig. 1. Distribution of CFI in patients with 0, 1, 2 or 3 vessel obstruction [45].
a large innate variance exists in the pre-existing collateral network in several organ systems. The most important determinant for the arteriogenic response in patients is the severity of the underlying arterial obstruction [42]. However, the correlation is relatively weak and within the same grade of arterial stenosis large inter-individual differences in the arteriogenic response have been documented. Pijls et al. measured CFI in 120 patients undergoing elective coronary angioplasty [43]. In their study, in 90 of 120 patients, ischemia was present at balloon inflation. Pohl et al. determined the extent of the collateral circulation in 450 patients with coronary artery disease [44]. They found that about two-thirds of the patients do not have enough collateral flow to prevent myocardial ischemia during coronary occlusion. In a large cohort study with over 800 patients, Meier also found that about two-thirds of patients have an under-developed collateral circulation which was associated with a higher cardiovascular mortality at 10 years follow-up [45]. They found Gaussian-like distributions of the extent of the collateral circulation, pointing again at innate differences. A modest shift to the right is observed when comparing the median CFI of patients with either single-, dual- or triple coronary artery disease to patients without
Frequency distribution (%)
35 CAD patients with CTO n= 97 Median CFI: 0.356
30 25 20 15 10 5 0 0-.1
.1-.2
.2-.3
.3-.4 .4-.5 .5-.6 .6-.7 Collateral flow index, CFI
.7-.8
.8-.9
.9-1
Fig. 2. Distribution of CFI in CAD patients with coronary total occlusion (CTO).
significant stenoses (Fig. 1). Only in patients with chronic total occlusion of a coronary artery, a strong shift to the right is observed, but again with large inter-individual differences. (Fig. 2, combined data from Prof. C. Seiler and our own database.) 5. Non-genetic determinants of coronary collateral flow Several environmental risk factors potentially influence the arteriogenic response in patients. Evidence for such relations has been provided by dedicated experimental disease models as well as by observations in patients (see Table 3). 5.1. Dyslipidemia Arteriogenesis is hampered in case of hypercholesterolemia as shown in rabbits and pigs. Using fluorescent microspheres, this delayed arteriogenic response was noticed in a rabbit model [46] of hypercholesterolemia, when compared to historic controls. In pigs, fed with a cholesterol-rich diet, the collateral response upon slowly progressive coronary artery obstruction was also delayed [47]. In patients, dyslipidemia was reported to be positively associated with spontaneously visible collateral arteries. This is probably related to more severe coronary artery disease [48]. 5.2. Hyperglycemia Hyperglycemia leads to changes in endothelial function, vascular smooth muscle cell proliferation and the interaction between vessel wall and circulating cells [49]. These processes are important in collateral artery formation and thus an effect of hyperglycemia appears conceivable. In one study, patients with diabetes developed less angiographically visible coronary collateral vessels than non-diabetic control patients [50]. However, a study using more accurate and quantitative CFI measurements in 100 diabetic patients and 100 non-diabetic patients contradicted this, revealing no difference in collateral function between the groups [51].
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Table 3 Non-genetic determinants of coronary collateral formation.
Dyslipidemia Hyperglycemia Hypertension Obesity Smoking Inflammation Aging
Experimental models
Patient studies
Inhibited collateral growth [47,46] Inhibited collateral growth [49] Promoted collateral growth [78] No direct evidence [53] Promoted collateral growth [79] Promoted collateral growth [56] Inhibited collateral growth [65,77,80,81]
No direct evidence Inhibited collateral growth [50]/no difference [51] Inhibited collateral growth [52] Inhibited collateral growth [53]/no direct evidence Promoted collateral growth [55]/no direct evidence Promoted collateral growth/inhibited collateral growth [62–64] Inhibited collateral growth [66, 67]
5.3. Hypertension
5.7. Aging
Evidence on the connection between collateral growth and hypertension is scarce. A high blood pressure increases shear stress. As shear stress is a main driving force of arteriogenesis, one hypothesis is that hypertension promotes collateral growth. However, hypertension is also associated with vascular dysfunction, likely reducing arterial remodelling and inhibiting collateral artery growth. In patients an inverse relation was found between high blood pressure and the extent of coronary collaterals in a cross-sectional study in 237 patients [52].
In a comparing study between C57BL/6 mice of 6 to 8 months and 22 to 24 months, left anterior descending coronary artery ligation was performed. The hearts were reperfused after 45 min whereupon the hearts were examined. A significant difference was found between infarct size in the young and old mice where the old mice showed larger infarcted areas [65]. In a study in 102 patients with an acutely occluded coronary artery, the extent of collateral development was determined. The patient group was divided into a ‘young’ and an ‘old’ group, and between the groups a significant difference was found with a higher prevalence of a well developed collateral circulation in the younger group [66]. In a cohort of 1934 patients with acute myocardial infarction, aging was recognized as being a factor predicting the number of collaterals present when vascular occlusion happens. The prevalence of collaterals decreased with age [67]. Taken together, both experimental data as well as clinical observations point to an important role for age in the arteriogenic response.
5.4. Obesity There are limited data regarding the link between obesity and arteriogenesis. Yilmaz et al. found a poorer coronary collateral circulation in obese patients with ischemic heart disease compared with patients not suffering from obesity [53]. Confounders in these findings may well be altered lipid profiles and insulin resistance which are often present in obese patients. Dyslipidemia, hyperglycemia, hypertension and obesity are components of the metabolic syndrome. Turhan et al. [54] concluded that patients with metabolic syndrome have impaired coronary collateral vessel development. No association was found between the presence of metabolic syndrome in 103 of 227 patients with coronary artery disease and formation of collateral vessels on angiography. 5.5. Smoking Clinical studies do not show a consistent relation between collateralization and smoking although one study found a positive association with the presence of collateral arteries on angiography [55]. The amount of pack years did not contribute, only current smoking status did. 5.6. Inflammation Arteriogenesis resembles inflammatory disease in many ways. The role of monocytes in arteriogenesis is well established [56, 57]. Also other immune cells like T-cells and natural killer-cells play an important role [58]. Treatment with pro-inflammatory compounds like lipopolysaccharide or tumor necrosis factor-alpha agonists enhances collateral artery growth [59]. When studying the role of monocyte chemotactic protein-1 (MCP-1) in acute myocardial infarction, plasma MCP-1 levels in patients were significantly higher in a group with well developed collaterals compared to a group with absent collateral circulation [60]. Interestingly, coronary collateral flow was associated with higher alpha-1-acid glycoprotein and C-reactive protein concentrations [61]. This underlines the role of acute phase proteins in collateral development. However, the finding on CRP was contradicted by several other studies, reporting that elevated CRP levels are associated with impairment of coronary collateralization [62-64].
6. Genetic determinants of collateral flow During the last years several efforts were made in both experimental as well as clinical studies to identify genetic factors that determine the arteriogenic response upon arterial obstruction. 6.1. Experimental models Several of the observations on genetic determinants of collateral artery growth are derived from experimental models of hindlimb ischemia. Lee et al. [68] extracted ribonucleic acid from adductor muscle in mice and used array expression profiling to determine the time course of differential expression of 12,000 genes after ligation of the femoral artery in C57BL/6 mice. Between the femoral artery ligation group and the sham group, 783 genes showed a differential expression where 518 were induced and 265 were repressed. Interestingly, a number of angiogenesis-related genes such as MCP1, placental growth factor and cysteine-rich protein-61, were differentially upregulated in the femoral artery ligation group as compared to the sham group. Also, a significant upregulation was found in genes thought to exert angiostatic activities, including interferon-gammainducible protein-10, monokine induced by interferon gamma and matrix metalloproteinase-12 in the ligated group. Of the different gene clusters, the inflammatory response-related genes cluster was the largest that was upregulated. Even though they were upregulated in both groups, the genes showed higher expression levels with longer duration in the femoral artery ligation versus the sham group. Wang et al. [3] executed a study to identify possible loci responsible for the variation in the arteriogenic response. In C57BL/6 × BALB/c F2 mice, cerebral collateral number and diameter were measured. After this, linkage analysis was carried out to identify quantitative trait loci (QTL) for collateral number and diameter. Collateral number and diameter were minimally correlated, consistent with Zhang et al. [69]
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and indicating that number and diameter are mainly independent traits. With genome wide logarithm of odds score profiling a highly significant locus on distal chromosome 7 was found for the collateral traits collateral number and collateral diameter. To confirm the major effect of chromosome 7, chromosome substitution was executed on A/J mice strain, which showed fewer pial collaterals than C57BL/6 mice and also a substantially smaller diameter. 6.2. Patients CD44 glycoproteins have a function as a receptor for leukocytes [70] as well as in the regulation of growth factor activation. In wild-type C57BL/6J mice, the expression of CD44 was found to be strongly increased in collateral arteries in the hind limb muscles [71]. CD44−/− mice showed a strong reduction in the arteriogenic response upon femoral artery ligation in comparison to the wildtype mice. Next, CD44 expression in patients was studied. In patients with a poor collateralization, CD44 expression was significantly decreased. These data showed that indeed expression differences can be detected between patients with either a poor or a well developed collateral circulation. This led to the design of a large RNA expression analysis study in patients. In a first cohort of 50 patients, CFI was measured and the group was divided into collateral responders and nonresponders. Blood samples were taken and genome-wide mRNA expression analysis was performed on monocytes. 244 differentially expressed genes were identified in stimulated monocytes. In the group of nonresponders, interferon-beta (IFN-beta) and other IFN-related genes demonstrated increased mRNA levels, linking IFN-beta to a hampered arteriogenic response. To validate the resulting hypothesis that IFN-beta attenuates arteriogenesis, perfusion was measured in a murine hindlimb model after ligation of the femoral artery. Significantly reduced arteriogenesis was displayed in mice treated with IFN-beta compared to controls. Furthermore, IFN-beta-receptor-1 knockout mice showed significantly better restoration of perfusion in the hindlimb 1 week after ligation compared to control mice in another study using microspheres. Finally, in an independent cohort of 50 patients with coronary total occlusion, again IFN-beta was strongly enriched in gene expression analysis [72]. At the same time Meier et al. performed a whole genome-analysis, using a larger population and also including subjects without coronary artery disease. They found differential expression of 203 genes which were involved in integrin, platelet-derived growth factor and transforming growth factor beta-signalling [73]. In a cohort of 226 patients (84 with and 142 without visible collaterals) nine single nucleotide polymorphisms (SNPs) were identified which potentially have effects on collateral formation [74]. These SNPs reflected genes involved in inflammation. Another factor that was recently distilled from patient data and experimentally validated is galectin-2. This factor is also overexpressed in patients with poor collateral arteries and exogenous application of this factor leads to a strong reduction in the arteriogenic response in the murine hindlimb model [75]. 7. Discussion The large variation between and within species in both the preexisting coronary collateral circulation as well as the arteriogenic response upon arterial occlusion strongly suggests that innate genetic factors are at stake, besides environmental factors. These differences can have strong implications for the choice of an experimental model. For example, when trying to induce collateral artery growth it is more appropriate to use a model of a relatively low innate arteriogenic response since otherwise it will be difficult to supersede this with a pharmacological compound. In more mechanistic studies,
when searching for factors that hamper collateral arteriogenesis, the opposite is true. Which model best mimics the clinical situation is difficult to tell since patients are very heterogenic, sometimes approaching pigs and sometimes coming closer to dogs regarding the collateral circulation. Interestingly, properties of the collateral circulation are consistent within different organ systems. That is, if the arteriogenic response is low in the coronary circulation, it is also low in the peripheral or the cerebral circulation. This notion is of clinical importance, although validation from patient databases (for example showing an association between cerebral and myocardial infarct size) are to the best of our knowledge not available. Also interesting is the fact that the capacity of the pre-existing collateral network does not always seem to relate to the arteriogenic response. Thus, different innate factors seem to be at stake for these two processes. Another important message is that not only the rate of proliferation determines the final capacity of the collateral circulation but also the morphological characteristics (large calibre capillaries versus true arterial connections) of the vasculature. Thus, it is not only a matter of quantity but also of quality. Recently, state-of-the art genomic and proteomic technologies identified several candidate genes responsible for the arteriogenic heterogeneity in patients. Given the complex multigenetic and lifestyle confounded nature of arteriogenesis, such genome wide technologies, combined with systems biology expectedly will propel the arteriogenic field into a new era of progress towards clinical application. Disclosures None. Acknowledgment We would like to thank Prof. Dr. C. Seiler for providing data on CFImeasurements in patients with a chronic total occlusion. References [1] Schaper W. Collateral circulation: past and present. Basic Res Cardiol 2009;104: 5–21. [2] Maxwell MP, Hearse DJ, Yellon DM. 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: 737–46. [3] Wang S, Zhang H, Dai X, Sealock R, Faber JE. Genetic architecture underlying variation in extent and remodeling of the collateral circulation. Circ Res 2010;107: 558–68. [4] Hale SL, Kloner RA. Effect of early coronary artery reperfusion on infarct development in a model of low collateral flow. Cardiovasc Res 1987;21:668–73. [5] Operschall C, Falivene L, Clozel JP, Roux S. A new model of chronic cardiac ischemia in rabbits. J Appl Physiol 2000;88:1438–45. [6] White FC, Carroll SM, Magnet A, Bloor CM. Coronary collateral development in swine after coronary artery occlusion. Circ Res 1992;71:1490–500. [7] Schaper W, Flameng W, Winkler B, Wusten B, Turschmann W, Neugebauer G, et al. Quantification of collateral resistance in acute and chronic experimental coronary occlusion in the dog. Circ Res 1976;39:371–7. [8] Heusch G, Skyschally A, Schulz R. The in-situ pig heart with regional ischemia/ reperfusion – ready for translation. J Mol Cell Cardiol 2011;50:951–63. [9] Eckstein RW. Coronary interarterial anastomoses in young pigs and mongrel dogs. Circ Res 1954;2:460–5. [10] Sjoquist PO, Duker G, Almgren O. Distribution of the collateral blood flow at the lateral border of the ischemic myocardium after acute coronary occlusion in the pig and the dog. Basic Res Cardiol 1984;79:164–75. [11] McDonough KH, Dunn RB, Griggs Jr DM. Transmural changes in porcine and canine hearts after circumflex artery occlusion. Am J Physiol 1984;246:H601–7. [12] Patterson RE, Kirk ES. Analysis of coronary collateral structure, function, and ischemic border zones in pigs. Am J Physiol 1983;244:H23–31. [13] Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S. An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. N Engl J Med 1992;327:1825–31. [14] Hedstrom E, Engblom H, Frogner F, Astrom-Olsson K, Ohlin H, Jovinge S, et al. Infarct evolution in man studied in patients with first-time coronary occlusion in comparison to different species – implications for assessment of myocardial salvage. J Cardiovasc Magn Reson 2009;11:38.
P.F.A. Teunissen et al. / Journal of Molecular and Cellular Cardiology 52 (2011) 897–904 [15] Bishop SP, White FC, Bloor CM. Regional myocardial blood flow during acute myocardial infarction in the conscious dog. Circ Res 1976;38:429–38. [16] Uemura N, Knight DR, Shen YT, Nejima J, Cohen MV, Thomas Jr JX, et al. Increased myocardial infarct size because of reduced coronary collateral blood flow in beagles. Am J Physiol 1989;257:H1798–803. [17] Chalothorn D, Faber JE. Strain-dependent variation in collateral circulatory function in mouse hindlimb. Physiol Genomics 2010;42:469–79. [18] Schaper W, Jageneau A, Xhonneux R. The development of collateral circulation in the pig and dog heart. Cardiologia 1967;51:321–35. [19] Unger EF. Experimental evaluation of coronary collateral development. Cardiovasc Res 2001;49:497–506. [20] Sato K, Laham RJ, Pearlman JD, Novicki D, Sellke FW, Simons M, et al. Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia. Ann Thorac Surg 2000;70:2113–8. [21] Carroll SM, White FC, Roth DM, Bloor CM. Heparin accelerates coronary collateral development in a porcine model of coronary artery occlusion. Circulation 1993;88: 198–207. [22] de Groot D, Grundmann S, Timmers L, Pasterkamp G, Hoefer IE. Assessment of collateral artery function and growth in a pig model of stepwise coronary occlusion. Am J Physiol Heart Circ Physiol 2011;300:H408–14. [23] Mills JD, Fischer D, Villanueva FS. Coronary collateral development during chronic ischemia: serial assessment using harmonic myocardial contrast echocardiography. J Am Coll Cardiol 2000;36:618–24. [24] 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. [25] Schwarz F, Wagner HO, Sesto M, Hofmann M, Schaper W, Kubler W. Native collaterals in the development of collateral circulation after chronic coronary stenosis in mongrel dogs. Circulation 1982;66:303–8. [26] Toyota E, Warltier DC, Brock T, Ritman E, Kolz C, O'Malley P, et al. Vascular endothelial growth factor is required for coronary collateral growth in the rat. Circulation 2005;112:2108–13. [27] Carrao AC, Chilian WM, Yun J, Kolz C, Rocic P, Lehmann K, et al. Stimulation of coronary collateral growth by granulocyte stimulating factor: role of reactive oxygen species. Arterioscler Thromb Vasc Biol 2009;29:1817–22. [28] Rugh KS, Garner HE, Hatfield DG, Miramonti JR. Ischaemia induced development of functional coronary collateral circulation in ponies. Cardiovasc Res 1987;21: 730–6. [29] Hoefer IE, van R N, Buschmann IR, Piek JJ, Schaper W. Time course of arteriogenesis following femoral artery occlusion in the rabbit. Cardiovasc Res 2001;49: 609–17. [30] Sheridan KM, Ferguson MJ, Distasi MR, Witzmann FA, Dalsing MC, Miller SJ, et al. Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 × Brown Norway hybrid rats. Am J Physiol Heart Circ Physiol 2007;293:H3498–505. [31] MacGabhann F, Peirce SM. Collateral capillary arterialization following arteriolar ligation in murine skeletal muscle. Microcirculation 2010;17:333–47. [32] Troidl C, Nef H, Voss S, Schilp A, Kostin S, Troidl K, et al. Calcium-dependent signalling is essential during collateral growth in the pig hind limb-ischemia model. J Mol Cell Cardiol 2010;49:142–51. [33] Pipp F, Boehm S, Cai WJ, Adili F, Ziegler B, Karanovic G, et al. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb. Arterioscler Thromb Vasc Biol 2004;24:1664–8. [34] Voskuil M, van R N, Hoefer IE, Seidler R, Guth BD, Bode C, et al. Modulation of collateral artery growth in a porcine hindlimb ligation model using MCP-1. Am J Physiol Heart Circ Physiol 2003;284:H1422–8. [35] Rakue H, Nakajima H, Katoh T, Usui M, Amemiya T, Miyagi M, et al. Low-dose basic fibroblast growth factor and vascular endothelial growth factor for angiogenesis in canine acute hindlimb insufficiency. Jpn Circ J 1998;62:933–9. [36] Fulton WF. Arterial anastomoses in the coronary circulation. II. Distribution, enumeration and measurement of coronary arterial anastomoses in health and disease. Scott Med J 1963;8:466–74. [37] Wustmann K, Zbinden S, Windecker S, Meier B, Seiler C. Is there functional collateral flow during vascular occlusion in angiographically normal coronary arteries? Circulation 2003;107:2213–20. [38] Bang OY, Saver JL, Buck BH, Alger JR, Starkman S, Ovbiagele B, et al. Impact of collateral flow on tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychiatry 2008;79:625–9. [39] Maas MB, Lev MH, Ay H, Singhal AB, Greer DM, Smith WS, et al. Collateral vessels on CT angiography predict outcome in acute ischemic stroke. Stroke 2009;40: 3001–5. [40] Abul-Khoudoud O. Diagnosis and risk assessment of lower extremity peripheral arterial disease. J Endovasc Ther 2006;13(Suppl 2):II10–8. [41] DeBakey ME, Simeone FA. Battle Injuries of the Arteries in World War II : An Analysis of 2,471 Cases. Ann Surg 1946;123:534–79. [42] Pohl T, Seiler C, Billinger M, Herren E, Wustmann K, Mehta H, et al. Frequency distribution of collateral flow and factors influencing collateral channel development. Functional collateral channel measurement in 450 patients with coronary artery disease. J Am Coll Cardiol 2001;38:1872–8. [43] Pijls NH, Bech GJ, el Gamal MI, Bonnier HJ, De BB, Van GB, et al. Quantification of recruitable coronary collateral blood flow in conscious humans and its potential to predict future ischemic events. J Am Coll Cardiol 1995;25: 1522–8. [44] Pohl T, Hochstrasser P, Billinger M, Fleisch M, Meier B, Seiler C. Influence on collateral flow of recanalising chronic total coronary occlusions: a case-control study. Heart 2001;86:438–43.
903
[45] Meier P, Gloekler S, Zbinden R, Beckh S, de Marchi SF, Zbinden S, et al. Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements. Circulation 2007;116:975–83. [46] van Royen N, Hoefer I, Buschmann I, Kostin S, Voskuil M, Bode C, et al. Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits. Cardiovasc Res 2003;57:178–85. [47] Boodhwani M, Nakai Y, Mieno S, Voisine P, Bianchi C, Araujo EG, et al. Hypercholesterolemia impairs the myocardial angiogenic response in a swine model of chronic ischemia: role of endostatin and oxidative stress. Ann Thorac Surg 2006;81: 634–41. [48] Kornowski R. Collateral formation and clinical variables in obstructive coronary artery disease: the influence of hypercholesterolemia and diabetes mellitus. Coron Artery Dis 2003;14:61–4. [49] Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation 2002;106:3037–43. [50] Abaci A, Oguzhan A, Kahraman S, Eryol NK, Unal S, Arinc H, et al. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 1999;99:2239–42. [51] Zbinden R, Zbinden S, Billinger M, Windecker S, Meier B, Seiler C. Influence of diabetes mellitus on coronary collateral flow: an answer to an old controversy. Heart 2005;91:1289–93. [52] Koerselman J, de Jaegere PP, Verhaar MC, van der Graaf Y, Grobbee DE. High blood pressure is inversely related with the presence and extent of coronary collaterals. J Hum Hypertens 2005;19:809–17. [53] Yilmaz MB, Biyikoglu SF, Akin Y, Guray U, Kisacik HL, Korkmaz S. Obesity is associated with impaired coronary collateral vessel development. Disord 2003;27: 1541–5. [54] Turhan H, Yasar AS, Erbay AR, Yetkin E, Sasmaz H, Sabah I. Impaired coronary collateral vessel development in patients with metabolic syndrome. Coron Artery Dis 2005;16:281–5. [55] Koerselman J, de Jaegere PP, Verhaar MC, Grobbee DE, van der Graaf Y. Coronary collateral circulation: the effects of smoking and alcohol. Atherosclerosis 2007;191: 191–8. [56] Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998;101: 40–50. [57] Heil M, Ziegelhoeffer T, Pipp F, Kostin S, Martin S, Clauss M, et al. Blood monocyte concentration is critical for enhancement of collateral artery growth. Am J Physiol Heart Circ Physiol 2002;283:H2411–9. [58] van W V, Toes RE, Seghers L, Deckers MM, de Vries MR, Eilers PH, et al. Natural killer cells and CD4+ T-cells modulate collateral artery development. Arterioscler Thromb Vasc Biol 2007;27:2310–8. [59] Grundmann S, Hoefer I, Ulusans S, van R N, Schirmer SH, Ozaki CK, et al. Antitumor necrosis factor-{alpha} therapies attenuate adaptive arteriogenesis in the rabbit. Am J Physiol Heart Circ Physiol 2005;289:H1497–505. [60] Park HJ, Chang K, Park CS, Jang SW, Ihm SH, Kim PJ, et al. Coronary collaterals: the role of MCP-1 during the early phase of acute myocardial infarction. Int J Cardiol 2008;130:409–13. [61] Brunetti ND, Correale M, Pellegrino PL, Cuculo A, Biase MD. Acute phase proteins in patients with acute coronary syndrome: correlations with diagnosis, clinical features, and angiographic findings. Eur J Intern Med 2007;18:109–17. [62] Gulec S, Ozdemir AO, Maradit-Kremers H, Dincer I, Atmaca Y, Erol C. Elevated levels of C-reactive protein are associated with impaired coronary collateral development. Eur J Clin Invest 2006;36:369–75. [63] Solorio S, Murillo-Ortiz B, Hernandez-Gonzalez M, Guillen-Contreras J, Arenas-Aranda D, Solorzano-Zepeda FJ, et al. Association Between Telomere Length and c-Reactive Protein and the Development of Coronary Collateral Circulation in Patients With Coronary Artery Disease. Angiology 2011 Aug;62(6):467–73. [64] Kerner A, Gruberg L, Goldberg A, Roguin A, Lavie P, Lavie L, et al. Relation of C-reactive protein to coronary collaterals in patients with stable angina pectoris and coronary artery disease. Am J Cardiol 2007;99:509–12. [65] Azhar G, Gao W, Liu L, Wei JY. Ischemia-reperfusion in the adult mouse heart influence of age. Exp Gerontol 1999;34:699–714. [66] Nakae I, Fujita M, Miwa K, Hasegawa K, Kihara Y, Nohara R, et al. Age-dependent impairment of coronary collateral development in humans. Heart Vessels 2000;15: 176–80. [67] Kurotobi T, Sato H, Kinjo K, Nakatani D, Mizuno H, Shimizu M, et al. Reduced collateral circulation to the infarct-related artery in elderly patients with acute myocardial infarction. J Am Coll Cardiol 2004;44:28–34. [68] Lee CW, Stabile E, Kinnaird T, Shou M, Devaney JM, Epstein SE, et al. Temporal patterns of gene expression after acute hindlimb ischemia in mice: insights into the genomic program for collateral vessel development. J Am Coll Cardiol 2004;43: 474–82. [69] Zhang H, Prabhakar P, Sealock R, Faber JE. Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cereb Blood Flow Metab 2010;30:923–34. [70] DeGrendele HC, Estess P, Siegelman MH. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 1997;278:672–5. [71] van R N, Voskuil M, Hoefer I, Jost M, de G S, Hedwig F, et al. CD44 regulates arteriogenesis in mice and is differentially expressed in patients with poor and good collateralization. Circulation 2004;109:1647–52. [72] Schirmer SH, Fledderus JO, Bot PT, Moerland PD, Hoefer IE, Baan Jr J, et al. Interferonbeta signaling is enhanced in patients with insufficient coronary collateral artery development and inhibits arteriogenesis in mice. Circ Res 2008;102:1286–94.
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P.F.A. Teunissen et al. / Journal of Molecular and Cellular Cardiology 52 (2011) 897–904
[73] Meier P, Antonov J, Zbinden R, Kuhn A, Zbinden S, Gloekler S, et al. Non-invasive gene-expression-based detection of well-developed collateral function in individuals with and without coronary artery disease. Heart 2009;95: 900–8. [74] Zhang J, Regieli JJ, Schipper M, Entius MM, Liang F, Koerselman J, et al. Inflammatory gene haplotype-interaction networks involved in coronary collateral formation. Hum Hered 2008;66:252–64. [75] van der Laan AM, Schirmer SH, de Vries MR, Koning JJ, Volger OL, Fledderus JO, et al. Galectin-2 expression is dependent on the rs7291467 polymorphism and acts as an inhibitor of arteriogenesis. Eur Heart J in press. doi:10.1093/eurheartj/ ehr220. Epub ahead of print. [76] Tang GL, Chang DS, Sarkar R, Wang R, Messina LM. The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia. J Vasc Surg 2005;41:312–20.
[77] Buschmann IR, Voskuil M, van R N, Hoefer IE, Scheffler K, Grundmann S, et al. Invasive and non-invasive evaluation of spontaneous arteriogenesis in a novel porcine model for peripheral arterial obstructive disease. Atherosclerosis 2003;167: 33–43. [78] Coyle P, Jokelainen PT. Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) and Wistar Kyoto (WKY) rats. Stroke 1983;14:605–11. [79] Heeschen C, Weis M, Cooke JP. Nicotine promotes arteriogenesis. J Am Coll Cardiol 2003;41:489–96. [80] Faber JE, Zhang H, Lassance-Soares RM, Prabhakar P, Najafi AH, Burnett MS, et al. Aging causes collateral rarefaction and increased severity of ischemic injury in multiple tissues. Arterioscler Thromb Vasc Biol 2011;31:1748–56. [81] Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, et al. Age-dependent impairment of angiogenesis. Circulation 1999;99:111–20.