OF THE CORONARY COLLATERAL CIRCULATION

1352 RELEVANCE Correspondene to: Professor Christian Seiler, University Hospital, Swiss Cardiovasular Center Bern, Freiburgstrasse, CH-3010 Bern, Switzerland; hristian.seiler.ardio@ insel.h C CORONARY DISEASE THE HUMAN CORONARY COLLATERAL CIRCULATION Christian Seiler Heart 2003; 89:1352 1357 ardiovasular diseases, in partiular oronary artery disease (CAD), are the leading ause of death in industrialised ountries. Established options for revasularisation inlude angioplasty and surgial bypass, both of whih are not suitable in 20230% of patients in whom the extent of oronary atheroslerosis is espeially severe. An alternative treatment strategy for revasularisation is therefore warranted both to ontrol symptoms as well as to alter the ourse of advaned CAD. An ideal andidate to fill in this gap is therapeuti promotion of oronary ollateral growth that is, the indution of natural bypasses. In order to reah this goal, a omprehensive understanding of the human oronary ollateral irulation with regard to its relevane, aurate assessment, the pathogeneti and pathophysiologial aspets, and the different therapeuti options is mandatory. OF THE CORONARY COLLATERAL CIRCULATION The oronary ollateral irulation has been reognised for a long time as an alternative soure of blood supply to a myoardial area jeopardised by ishaemia. More than 200 years ago, Heberden desribed a patient who had been nearly ured of his angina petoris by sawing wood eah day, w1 a phenomenon alled warm up or first effort angina whih was traditionally asribed to oronary vasodilation with opening of ollateral vessels to support the ishaemi myoardium. Alternatively, and more reently, walk through angina has been interpreted as a biohemial (that is, ishaemi preonditioning) rather than a biophysial (that is, ollateral reruitment) event leading to heightened tolerane against myoardial ishaemia. Both mehanisms probably ontribute to the desribed phenomenon, whih is easily obtainable by areful history taking of the patient. 1 Aside from the ontroversies just alluded to, there have been numerous investigations demonstrating a protetive role of well versus poorly grown ollateral arteries (fig 1) showing smaller infarts, w2 less ventriular aneurysm formation, improved ventriular funtion, w2 fewer future ardiovasular events, 2 and improved survival. 3 However, the funtional relevane of oronary ollateral vessels in humans had also been a matter of debate for many years. w3 Muh of this ontroversy was likely the result of inadequate means for gauging human oronary ollaterals and the investigation of populations too small to be representative for all the patients with CAD. The latter is well illustrated by the fat that among patients with haemodynamially signifiant atherosleroti lesions, only about a third have funtionally suffiient oronary ollaterals whih are able to prevent signs of myoardial ishaemia during brief vasular olusions (fig 2 4 ). In the absene of stenoses, it has been traditionally assumed that oronary arteries are funtional end arteries. w4 Using diret and quantitative intraoronary ollateral measurements (see below), it has, however, been doumented very reently that the notion of the human oronary irulation being built without preformed funtioning anastomoses between vasular territories is a myth rather than reality; in the absene of obstrutive CAD or even in entirely normal hearts, there has been ollateral flow to a briefly oluded oronary artery suffiient to prevent ECG signs of myoardial ishemia in 20225% of the population studied (fig 2). 5 ASSESSMENT Natural oronary olusion model (hroni total olusion model) In the situation of a spontaneously ourring oronary artery olusion without myoardial infartion, a well developed ollateral irulation must be the reason for the salvaged ardia musle. A pathophysiologial alternative to this senario is indiated by the following equation desribing infart size (IS), and it onsists of an exeedingly small ishaemi myoardial area at risk (AR) w5 : IS = oronary olusion time 6 AR 6 ollateral supply 21 The entire filling of a hronially oluded, ollateral reeiving (that is, ipsilateral) oronary artery from a ollateral supplying (that is, ontralateral) vessel (fig 1) illustrates that AR is losely and inversely dependent on ollateral flow, to the extent that the AR of a ertain vessel may Heart: first published as 10.1136/heart.89.11.1352 on 31 Otober 2003. Downloaded from http://heart.bmj.om/ on 27 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

disappear in the presene of well grown ollaterals. The validity of the onept desribed in the above equation has been reently onfirmed in the linial setting by doumenting that oronary olusion time no longer plays a role as a preditor for IS in the presene of a ollateral relative to normal flow (ollateral flow index; see below) > 25%. 6 Thus, to detet normal ventriular wall motion in the presene of a proximal or mid hroni olusion represents a way of qualifying good ollateral flow. The major disadvantage of this qualitative method for ollateral assessment is that it requires oronary angiography to detet vasular olusion. Having established the diagnosis of an entirely bloked oronary artery, various myoardial perfusion traers (different radioative traers, ehoontrast media) are in priniple appropriate to measure the gold standard of ollateral funtion (that is, absolute perfusion in ml/min/g of tissue) non-invasively by positron emission tomography or Doppler w6 w7 ehoardiography. Artifiial oronary olusion model (angioplasty model) At present, invasive ardia examination is a prerequisite for reliable qualitative or quantitative assessment of oronary ollaterals. In the natural olusion model, it is needed to onfirm total vasular obstrution, and in the artifiial olusion model, it is essential for briefly bloking the vessel using an angioplasty balloon atheter. In addition, systematially onsistent and exlusive ollateral haraterisation (fig 3) requires the permanent or temporary olusion of the epiardial ollateral reeiving artery, yielding the so alled reruitable as opposed to spontaneously visible ollateral flow. Employing the angioplasty model, there are several qualitative and quantitative methods subsequently desribed whih an be used to haraterise the ollateral irulation. Angina petoris and intraoronary ECG during vessel olusion The simplest but rather impreise way to qualify ollateral vessels is to ask the patient about the presene of angina petoris shortly before the end of arterial balloon olusion. Figure 1 Coronary angiogram with injetion of radiographi ontrast medium into the right oronary artery (RCA) and omplete filling of the proximally oluded (red irle) left anterior desending oronary artery (LAD) via ollateral hannels (arrows). The preditive value of absent or present hest pain for ollaterals suffiient or insuffiient, respetively, to prevent ishaemia as deteted by intraoronary ECG (fig 4) is rather low. 7 The use of an intraoronary ECG lead obtained via the angioplasty guidewire for ollateral assessment provides a good representation of the pertinent myoardial area. Intraoronary ECG ST segment hanges of. 0.1 mv onstitute the definition of ollaterals insuffiient to prevent ishaemia in the respetive myoardial territory. 7 Angiographi methods The oronary angiographi method for ollateral qualifiation most widely used is similar but not idential to the one first desribed by Rentrop and olleagues. 8 The latter provides a sore from 0 3 for reruitable ollateral vessels upon olusion of the ipsilateral artery, the former an idential sore for spontaneously visible ollaterals without artifiial vasular olusion. The sore desribes epiardial oronary artery filling with radiographi ontrast dye via ollaterals as follows: 0 = no filling; 1 = small side branhes filled; 2 = major side branhes of the main vessel filled; 3 = main vessel entirely filled. The fat that in linial routine, just spontaneously visible ollaterals are sored further impairs the method s sensitivity whih is quite blunt already. Reruitable ollateral vessel grading in the absene of hroni oronary olusion, however, requires the insertion of two oronary atheters that is, one for balloon olusion of the ollateral reeiving vessel and the seond for injetion of ontrast dye into the ollateral supplying artery. An alternative, semi-quantitative angiographi method onsists of determining the number of heart beats during oronary olusion needed to wash out the angiographi medium injeted into the ipsilateral artery immediately before balloon olusion (that is, washout ollaterometry 9 ). The ontrast dye aught distal to the olusive balloon an only be washed out by ollateral flow. A washout time of ( 11 heart beats aurately predits ollaterals suffiient to prevent ishaemia during a brief oronary olusion. Intraoronary pressure or Doppler sensor measurements Today, pressure or Doppler sensor-tipped angioplasty guidewires are available whih are almost equivalent to regular guidewires in their handling properties. The theoretial basis for the use of intraoronary pressure or blood flow veloity measurements to determine ollateral flow relates to the fat that perfusion pressure (. entral venous bak pressure) or veloity signals obtained distal to an oluded stenosis originate from ollaterals (fig 3). The measurement of aorti and intraoronary pressure or veloity provides the basi variables for the alulation of a pressure derived or veloity derived ollateral flow index (CFI), 7 both of whih express the amount of flow via ollaterals to the vasular region of interest as a fration of the flow via the normally patent vessel. Pressure derived CFI is determined by simultaneous measurement of mean aorti (P ao ), mean distal oronary olusive (P ol ), and entral venous pressure (CVP) (fig 4): CFI = (P ol 2 CVP)/(P ao 2 CVP). Veloity derived CFI is measured by obtaining distal olusive oronary flow veloity (V ol ) and oronary flow veloity during vessel pateny (V Øol ) taken at the same loation and following olusion indued reative hyperaemia: CFI = V ol /V Øol. CFI measurements have been doumented to be very aurate with regard to ECG derived dihotomous ollateral assessment, 1353 Heart: first published as 10.1136/heart.89.11.1352 on 31 Otober 2003. Downloaded from http://heart.bmj.om/ on 27 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

1354 with regard to eah other, but also to quantitative 99m Tsestamibi imaging during balloon olusion. 7 10 Pressure and Doppler derived intraoronary ollateral measurements are regarded as the referene method for linial assessment of oronary ollateral flow. PATHOGENESIS Clinial or environmental fators onsistently desribed as influening the development of oronary ollaterals in humans are the severity of oronary artery stenoses, 4 8 11 and the duration of myoardial ishaemi symptoms. 11 Conversely, there has been disordant information about the influene of metaboli disorders on ollateral development suh as diabetes mellitus. w8 10 In our experiene enompassing 437 non-diabeti and 89 diabeti patients who underwent intraoronary ollateral flow measurements, CFI (see above) is pratially idential: mean (SD) 0.215 (0.146) and 0.209 (0.128), respetively (p = 0.71). A possible relevane of holesterol metabolism on the expansion of the ollateral irulation has been indiated only experimentally. w11 The presene of systemi hypertension Figure 3 Diagram illustrating the priniple of ollateral assessment during oronary artery balloon olusion using an angioplasty sensor guidewire (blue line). This pressure or Doppler guidewire is positioned distal to the oluded site. Pressure signals (exept for venous bak pressure) or flow veloity signals deteted during vasular olusion originate from ollateral vessels supplying the bloked vasular region. Figure 2 Frequeny distribution (per ent of the entire population, vertial axis) of ollateral flow obtained during oronary artery balloon olusion relative to normal flow during vessel pateny (ollateral flow index, horizontal axis). The left panel shows the distribution in 500 patients with haemodynamially relevant oronary artery stenoses. In the right panel, the distribution in 120 individuals without oronary stenoses is depited. has also been suggested to promote well grown ollaterals. Previous studies on the pathogenesis of ollateral vessels in humans have often laked suffiient patient numbers and/or quantitative means for ollateral assessment. Although oronary stenosis severity is the independent preditor for ollateral development in humans, CFI may vary for a given stenosis of, for example, 95% diameter narrowing between 0.0 and 0.70. 4 Conversely, in the absene of a oronary artery stenoti lesion, CFI ranges between 0.0520.4. 5 Therefore, aside from the environmental fators just desribed, the influene of a ertain geneti bakground or the temporarily varying up/down regulation of genes on the formation of well ondutive ollateral arteries even before the start of CAD must be very relevant, but so far only rarely investigated. w12 FUNCTIONAL ASPECTS Funtional, haemodynami or biophysial aspets of well grown ollateral arteries relate to the fat that they onstitute a network within the oronary irulation (fig 3). Suh onnetions between adjaent vasular territories together with spatially varying vasular resistanes to blood flow w13 are the basis for pathophysiologial aspets of ollaterals rarely onsidered, suh as the redistribution of blood during vasodilation away from a region in need (that is, oronary steal 12 ), the derease in ollateral flow to a ertain vasular region following reanalisation of a hronially oluded oronary artery, w14 and the enhaned risk of oronary restenosis following perutaneous oronary intervention in the presene of high and ompetitive ollateral flow to this area. w15 The latter situation is similar to that of ompetitive flow between a barely stenoti oronary artery and a bypass graft to this vessel whih was unneessarily implanted; usually, the lifespan of suh a bypass is very muh abridged. Regarding the vasomotor response of ollateral arteries, experimental studies have shown that physial exerise indues a more than twofold perfusion inrease in ollateral dependent myoardium via b adrenergi and nitri oxide mehanisms. w16 In up to 50% of patients with hroni total oronary artery olusions, there may be no infarted myoardium within the vasular territory supplied by the bloked vessel. It is unknown how many suh patients remain ompletely asymptomati, and therefore must have a normal ollateral oronary flow reserve{that is, the apaity to augment flow in response to inreased myoardial demand. However, some of the patients with hroni total olusions without myoardial infartion suffer from hest pain on Heart: first published as 10.1136/heart.89.11.1352 on 31 Otober 2003. Downloaded from http://heart.bmj.om/ on 27 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

exertion, and they have been found, using positron emission tomography, to exert a redued ollateral dependent flow reserve in response to dipyridamole. 13 Interestingly, the same patients also revealed impaired systoli funtion in the ollateral supplied left ventriular region as opposed to individuals with maintained ollateral oronary flow reserve featuring normal regional wall motion. THERAPEUTIC PROMOTION An alternative treatment strategy is needed in 20230% of patients with CAD in whom the extent of oronary atheroslerosis is too severe to allow onventional revasularisation. Therapeuti angiogenesis/arteriogenesis are new strategies for revasularising ishaemi myoardial tissue by formation of natural bypasses that is, ollateral vessels. Understanding the many steps and regulatory mehanisms of angio- and arteriogenesis as opposed to vasulogenesis is important for designing suh strategies. Abbreviations AR: area at risk for myoardial infartion BFGF: basi fibroblast growth fator CAD: oronary artery disease CFI: ollateral flow index (no unit) CVP: entral venous pressure (mm Hg) GM-CSF: granuloyte2marophage olony stimulating fator IS: infart size P ao : mean aorti pressure (mm Hg) P ol : mean oronary olusive or wedge pressure (mm Hg) VEGF: vasular endothelial growth fator V ol : intraoronary olusive blood flow veloity (m/s) V Øol : intraoronary non-olusive blood flow veloity (m/s) Figure 4 Simultaneous reordings of an intraoronary (i..) ECG lead (top), phasi (left side) and mean (right side) aorti (P ao, mm Hg), oronary olusive (P ol, mm Hg), and entral venous pressures (CVP, mm Hg). P ao is gauged via a 6 Frenh oronary artery guiding atheter, P ol via a pressure guidewire positioned distal of a stenosis to be dilated, and CVP via a right atrial atheter. To the right of the phasi pressure traings obtained during oronary artery pateny, mean pressures are reorded during and after angioplasty balloon deflation. During inflation, there are pronouned ECG ST segment elevations (arrows) indiating ollateral vessels insuffiient to prevent myoardial ishaemia. Collateral flow index (CFI) is alulated as follows: CFI = (P ol 2 CVP)/(P ao 2 CVP). Vasulogenesis The initial steps in the formation of the vasular system during embryoni life involve the differentiation of mesodermal ells into angioblasts that give rise to endothelial ells forming the first primitive blood vessels. 14 Angiogenesis New vessels an subsequently develop from the pre-existing plexus by sprouting and intussuseption. This formation of new vessels from pre-existing ones has been alled angiogenesis. w17 In addition to endothelial ells, periytes (for apillaries) and smooth musle ells (for larger vessels) are neessary for the maturation of these newly growing vessels. w17 Angiogenesis and arteriogenesis are not restrited to the growing organism. Tissue repair and regeneration (for Relevane and assessment of oronary ollaterals: key points Well developed oronary ollateral arteries in patients with CAD mitigate myoardial infarts with less ventriular aneurysm formation and improved ventriular funtion, redue future ardiovasular events, and improve survival Collateral arteries preventing myoardial ishaemia during brief vasular olusion are present in a third of patients with CAD Among individuals without relevant oronary stenoses, there are preformed ollateral arteries preventing myoardial ishaemia in 20 25% Collateral flow suffiient to prevent myoardial ishaemia during oronary olusion amounts to > 25% of the normal flow through the open vessel Myoardial infart size is a produt of oronary artery olusion time, area at risk for infartion, and the inverse of ollateral supply Coronary ollateral flow an be assessed only during vasular olusion of the ollateral reeiving artery Presently, the gold standard for linial oronary ollateral assessment is the measurement of intraoronary olusive pressure or veloity derived ollateral flow index whih expresses ollateral flow as a fration of flow during vessel pateny 1355 Heart: first published as 10.1136/heart.89.11.1352 on 31 Otober 2003. Downloaded from http://heart.bmj.om/ on 27 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

1356 example, wound healing and the yli hanges of the female reprodutive system) are manifestations of angiogenesis. New apillaries form around zones of tissue ishaemia, as ours in myoardial infartion and stroke. However, vessel formation and growth is also a part of pathogeni proesses like proliferative retinopathies, psoriasis, haemangiomas, tumours, and atherosleroti plaques. 15 Upon angiogeni stimulation for example, after tissue injury or ishaemia with hypoxia and hypoglyaemia growth fators and inflammatory mediators are released loally leading to vasodilation, enhaned vasular permeability, and aumulation of monoytes and marophages whih in turn serete more growth fators and inflammatory mediators. w18 These inflammatory ells release metalloproteinases that dissolve the surrounding matrix and the basal membrane of the preformed vessel. Hypoxia sensitises the loal endothelial ells to the hemotati and proliferative effets of various growth fators by upregulating their reeptors. Endothelial ells detah from their neighbours, migrate, proliferate, and subsequently form a new vessel with a lumen. Periytes and smooth musle ells are also involved in this proess. Arteriogenesis Cardiologists have long been aware of the ourrene of large and often epiardial ollateral vessels after total or subtotal olusion of a major oronary artery (fig 1). These usually beome visible within two weeks following an olusion, and they arise from preformed arterioles. The remodelling proess involved in this reruitment of already existing ollateral vessels has been termed arteriogenesis. 16 Large bridging ollaterals are likely to be muh more effetive in salvaging ishaemi myoardium at risk for nerosis than small periishaemi apillaries. The omplete obstrution of a oronary artery leads to a fall in post-stenoti pressure and to a redistribution of blood to pre-existing arterioles. The resulting streth and shear fores may lead to an inreased expression of ertain endothelial hemokines, adhesion moleules, and growth fators. Within days, irulating monoytes attah to the endothelium of the bridging ollateral vessels ausing a loal inflammatory reation. w18 Matrix dissolution ours and the vessels undergo a growth proess with ative proliferation of their endothelial and smooth musle ells. Growth fator andidates A variety of physiologial moleules have been identified that appear to promote angio- and arteriogenesis. Most at by stimulating migration and proliferation of endothelial ells and/or smooth musle ells, like the family of fibroblast growth fators (FGF) and vasular endothelial growth fators (VEGF). Both ause vasodilation by stimulating the release of nitri oxide. It is therefore important in animal as well as linial studies to differentiate between improved perfusion aused merely by vasodilation and true ollateral growth. Other growth fator andidates inlude plaental growth fator, angiopoietin 1, transforming growth fator b, platelet derived growth fator, and about half a dozen other ytokines, proteases, and proteins. 15 Arteriogenesis has been shown to be indued by ativated marophages, w19 by lipopolysaharide, w18 monoyte hemotati protein-1, 16 tumour nerosis fator a, FGF, and also via granuloyte2 marophage olony stimulating fator (reombinant human 14 17 GM-CSF; Molgramostim). Pathogenesis and promotion of oronary ollaterals: key points Clinial variables prediting the development of ollateral arteries are the haemodynami severity of oronary stenoses and the duration of myoardial ishaemi symptoms 25230% of patients with CAD annot be revasularised by perutaneous oronary intervention or oronary artery bypass grafting; therapeuti promotion of ollateral growth appears to be a valuable treatment strategy in those patients Promotion of ollateral growth should aim at induing the development of large ondutive ollateral arteries (that is, arteriogenesis) and not so muh the sprouting of apillary-like vessels (that is, angiogenesis) So far, the largest, ontrolled linial angiogenesis trials on the effiay of VEGF and basi FGF have been negative with regard to treadmill exerise time and myoardial sintigraphi data Large ondutive ollateral arteries (that is, arteriogenesis) appear to be effetively promoted via the ativation of monoytes/marophages Clinial studies Angiogenesis may be indued by surgial or atheter based delivery of various promotors, suh as VEGF and FGF, angiogeni agents most often used in urrent linial studies. w20 w21 Although animal studies have established the priniple that ollateral funtion improves after delivering angiogeni growth fators, w22 and although the first unontrolled linial studies have demonstrated the safety and feasibility of VEGF and basi FGF, w23 effiay data of angiogeni therapy have been sare and ontroversial. The most reent and largest ontrolled linial trials using VEGF165 (VIVA: VEGF in ishemia for vasular angiogenesis 18 ) and FGF2 (FIRST: FGF initiating revasularization trial 19 ) in 178 and 337 patients with CAD, respetively, have not shown an effet on the study end points that is, treadmill exerise time, angina petoris at 60 and 120 days (VIVA), and, respetively, exerise tolerane test duration at 90 day follow up and hanges in the magnitude of myoardial ishaemia by T99m SPECT. Controversy over the ability of angiogeni growth fators to promote oronary ollaterals is likely due to the use of end points for their assessment whih are too blunt to disern subtle hanges in ollateral flow. At this early phase of linial angiogeni/arteriogeni therapy during whih sreening for the most effetive growth fator among more than a dozen andidates has not even started properly, seletion of the best agents ought to be based on aurate and diret invasive measurements of oronary ollateral flow (figs 3 and 4) that is, the variable hypothesised to be positively influened by the growth fators. Equally important, angiogeni fators may have been employed whih indue the formation of small, high resistane apillaries (angiogenesis) rather than large interonneting arterioles (arteriogenesis) whih are required for the salvage of myoardium in the presene of olusive CAD. In the first randomised, plaebo ontrolled linial trial, GM-CSF has been shown to be effetive with regard to sequentially and invasively obtained ollateral flow among 21 patients with CAD. 20 Heart: first published as 10.1136/heart.89.11.1352 on 31 Otober 2003. Downloaded from http://heart.bmj.om/ on 27 Marh 2019 by guest. Proteted by opyright. www.heartjnl.om

Arteriogenesis is related to enhaned shear fores at the vessel wall in response to inreased flow through pre-existing ollateral onnetions. Therefore, physial exerise would be an ideal therapeuti option for induing arteriogenesis, beause ardia output and thus oronary flow is elevated along the arterial branhes of the oronary irulation during exerise. So far, the only prospetive investigation in humans on the effet of exerise regarding ollateral growth has employed an insensitive instrument for ollateral assessment that is, angiographi imaging of spontaneously visible ollateral vessels and has been negative. w24 Preliminary data from our own laboratory suggest that even in the absene of CAD, ollateral flow, as assessed by intraoronary pressure derived measurements, is augmented substantially in response to endurane exerise training. w25 REFERENCES 1 Billinger M, Fleish M, Eberli FR, et al. Is the development of myoardial tolerane to repeated ishemia in humans due to preonditioning or to ollateral reruitment? J Am Coll Cardiol 1999;33:1027 35. A pathophysiologial study in 30 patients undergoing oronary angioplasty on the respetive ontribution of ollateral reruitment and ishaemi preonditioning to the development of ishaemi tolerane in response to repetitive oronary olusions. 2 Billinger M, Kloos P, Eberli F, et al. Physiologially assessed oronary ollateral flow and adverse ardia ishemi events: a follow-up study in 403 patients with oronary artery disease. J Am Coll Cardiol 2002;40:1545 50. 3 Hansen JF. Coronary ollateral irulation: linial signifiane and influene on survival in patients with oronary artery olusion. Am Heart J 1989;117:290 5. The only study of survival rates in patients with CAD and well versus poorly developed oronary ollateral vessels as assessed by angiography. 4 Pohl T, Seiler C, Billinger M, et al. Frequeny distribution of ollateral flow and fators influening ollateral hannel development. Funtional ollateral hannel measurement in 450 patients with oronary artery disease. J Am Coll Cardiol 2001;38:1872 8. 5 Wustmann K, Zbinden S, Windeker S, et al. Is there funtional ollateral flow during vasular olusion in angiographially normal oronary arteries? Cirulation 2003;107:2213 20. 6 Lee CW, Park SW, Cho GY, et al. Pressure-derived frational ollateral blood flow: a primary determinant of left ventriular reovery after reperfused aute myoardial infartion. J Am Coll Cardiol 2000;35:949 55. An elegant study proving the onept of the investigation by Reimer and olleagues w5 in 70 patients with aute myoardial infartion undergoing primary angioplasty and pressure derived ollateral flow index (CFI) measurement. Left ventriular reovery was primarily dependent on CFI, and time to reperfusion was not related to wall motion reovery in patients with CFI > 0.24. 7 Seiler C, Fleish M, Garahemani A, et al. Coronary ollateral quantitation in patients with oronary artery disease using intravasular flow veloity or pressure measurements. J Am Coll Cardiol 1998;32:1272 9. 8 Rentrop KP, Cohen M, Blanke H, et al. Changes in ollateral hannel filling immediately after ontrolled oronary artery olusion by an angioplasty balloon in human subjets. J Am Coll Cardiol 1985;5:587 92. First desription of oronary angiographi grading obtained during balloon olusion for haraterising ollateral vessel filling. In 16 patients undergoing oronary angioplasty, ollateral filling to the artery being dilated was visualised by ontrast injetion into the ontralateral artery using a seond arterial atheter. 9 Seiler C, Billinger M, Fleish M, et al. Washout ollaterometry: a new method of assessing ollaterals using angiographi ontrast learane during oronary olusion. Heart 2001;86:540 6. 10 Matsuo H, Watanabe S, Kadosaki T, et al. Validation of ollateral frational flow reserve by myoardial perfusion imaging. Cirulation 2002;105:1060 5. Twenty four onseutive patients with single left anterior desending oronary artery stenosis underwent pressure derived CFI measurement. It was ompared with the extent and severity of the defet during oronary olusion using (99m)T-sestamibi imaging at balloon inflation of the respetive oronary artery. The authors onluded that pressure derived CFI is highly orrelated with the extent and severity of the defet at myoardial perfusion of the territory of the oluded artery. 11 Piek JJ, Koolen JJ, Hoedemaker G, et al. Severity of single-vessel oronary arterial stenosis and duration of angina as determinants of reruitable ollateral vessels during balloon olusion. Am J Cardiol 1991;67:13 17. 12 Seiler C, Fleish M, Meier B. Diret intraoronary evidene of ollateral steal in humans. Cirulation 1997;96:4261 7. 13 Vanovershelde JLJ, Wijns W, Depré C, et al. Mehanisms of hroni regional postishemi dysfuntion in humans. New insights from the study of non-infarted ollateral-dependent myoardium. Cirulation 1993;87:1513 23. 14 Carmeliet P. Mehanisms of angiogenesis and arteriogenesis. Nature Med 2000;6:389 95. In this review, the ellular and moleular mehanisms underlying the formation of endothelium lined hannels (angiogenesis) and their maturation via reruitment of smooth musle ells (arteriogenesis) during physiologial and pathologial onditions are summarised, along with possible therapeuti appliations. 15 Folkman J. Angiogenesis in aner, vasular, rheumatoid and other disease. Nature Med 1995;1:27 31. Review on the onept of the swith to the angiogeni phenotype in tumorigenesis as a net balane of positive and negative regulators of blood vessel growth. The extent to whih the negative regulators are dereased during this swith may ditate whether a primary tumour grows rapidly or slowly and whether metastases grow at all. 16 Ito WD, Arras M, Winkler B, et al. Monoyte hemotati protein-1 inreases ollateral and peripheral ondutane after femoral artery olusion. Cir Res 1997;80:829 37. Twelve rabbits were designated to reeive monoyte hemotati protein-1 (MCP-1), plaebo, or no infusion. Seven days after femoral artery olusion, ollateral and peripheral ondutanes were measured and found to be signifiantly elevated in animals with MCP-1 treatment ompared with the ontrol group. In this study, the term arteriogenesis was introdued. 17 Bushmann I, Hoefer I, van Royen N, et al. GM-CSF: a strong arteriogeni fator ating by amplifiation of monoyte funtion. Atheroslerosis 2001;159:343 56. 18 Henry TD, Annex BH, MKendall GR, et al. The VIVA trial. Vasular endothelial growth fator in ishemia for vasular angiogenesis. 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