Mike J L DeJongste, René A Tio, Robert D Foreman

See end of artile for authors affiliations Correspondene to: Dr Mike J L DeJongste, Department of Cardiology, Thoraxenter, University Hospital of Groningen, PO Box 30,001, 9700 RB Groningen, The Netherlands; m.j.l.de.jongste@ thorax.azg.nl Coronary disease CHRONIC THERAPEUTICALLY REFRACTORY ANGINA PECTORIS ATHEROSCLEROSIS, I Mike J L DeJongste, René A Tio, Robert D Foreman Heart 2004; 90:225 230. doi: 10.1136/hrt.2003.025031 n ontrast to the tremendous inrease in pratial opportunities and theoretial knowledge in the western world, resulting in a doubling of our average life expetany, the number of diseases has not been redued during the last 150 years. This apparent ontradition, seondary to hanges in environmental influenes and soioultural developments suh as smoking habits, sedentary lifestyles, fast food meals, stressful jobs, et, have led to the introdution of newer definitions for illnesses. From this perspetive, the illness pattern has hanged during the last entury and a half from infetious diseases to more ulturally influened diseases, suh as oronary artery disease (CAD). However, to date, following thorough researh, no evidene is available that these ultural influenes are the sole initiators in the proess of atherosleroti plaque formation. Albeit that plaque formation is the result of a variety of proesses ulminating in CAD, the searh for the initial trigger is ongoing. During the last few years, more and more evidene has beome available that an inflammatory response plays a key role in atherosleroti plaque formation leading to CAD. These mediators of inflammation interat with nervous signalling transdution pathways arising from the environment of the atherosleroti plaque. The inflammatory substanes released during myoardial ishaemia are relevant to progression of the atherosleroti proess in the narrowed oronary arteries. In ontrast, the reruited nervous and neurohumoral pathways during ardia ishaemi hallenges are thought to be involved in maintaining the integrity of the myoytes. Subsequently, myoardial ishaemia, angina petoris signalling pathways, and neurohumoral and inflammatory responses are onsidered to be key players in atherosleroti heart disease. This artile disusses newer insights into the pathophysiology of hroni (refratory) angina petoris, resulting from stable atherosleroti CAD, and suggests some potential additional treatments. ANGINA PECTORIS, AND MYOCARDIAL ISCHAEMIA Atheroslerosis During the initial phase in the atherosleroti proess, the vasular wall thikens in onjuntion with luminal dilatation (that is, vasular remodelling). Though in stable situations many (risk) fators determine the veloity of progression to plaque formation, before a ritial stenosis in a oronary artery is formed an olusion may already our, resulting from an unstable plaque. Given the gradual redution in luminal diameter of a oronary artery aused by atherosleroti plaque formation, the inreased oxygen demand of the heart during exerise ultimately results in a perturbation of the balane between myoardial oxygen onsumption (O 2 demand) and oronary blood flow (O 2 supply), the so-alled ishaemi threshold. 1 Subsequently, during a physial work out, the ishaemi threshold is determined at the moment oronary flow and myoardial oxygen onsumption beome disproportional. Pharmaologial treatments and revasularisation proedures are meant to improve this ishaemi threshold, by reduing the myoardial oxygen demand, or by improving the oxygen supply to the myoardium. Reruited pathways following myoardial ishaemia Before the disturbane in oxygen supply and demand balane ours in the heart, in stable irumstanes and predominantly during physial exerise, sensitisation of high threshold nerve endings in the myoardium takes plae through a variety of metaboli substanes suh as potassium, latate, adenosine, bradykinin, and prostaglandins. 2 These substanes indue various kinds of sensations suh as fatigue, musle pain, and shortness of breath. The ardiorespiratory threshold that limits exerise is determined by metaboli exitation ontration (Na + K + ) alterations induing musle tension, sensation of weakness or fatigue, and finally the responsiveness of motor neurone ommands. 3 The responsiveness of motor neurones, depending on impulses relayed by the spinothalami trat to medullar neurones of the ardiorespiratory entres, is influened by entral (that is, reflexes in the spinal ord) and peripheral fators (that is, 225 Heart: first published as 10.1136/hrt.2003.025031 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 24 November 2018 by guest. Proteted by opyright.

226 reeptors in the musles). Furthermore, exerise in ardiovasular ompromised patients initiates stimulation of the b sympatheti nervous system, resulting in partial ounteration of the limited exerise by an inreased heart rate and ventilation frequeny. However, the adaptive effet to ishaemi hallenges in humans appears to be oordinated by a adrenergi reeptors. 4 It has been reported that a speifi G i protein, onneted to the a 2 reeptors, indues atherosleroti related impairment of endothelium dependent relaxation. Furthermore, a reeptors, loalised on primary afferents, sympatheti postganglioni neurones, and dorsal laminae of the spinal ord and of the brainstem are involved in analgesia and play a role in vasomotor ontrol. In brief, the role of a adrenergi reeptors in myoardial ishaemia, by ontrolling vasomotor tone, is well established. The role of the vagus nerve in proessing noxious ardia information remains ontroversial. While both vagal and sympatheti afferent fibres ontribute to the inreased ativity of spinothalami trat ells and spinal neurons in the C1 C3 segments of the spinal ord, vagal stimulation is a more potent stimulus. Ativation of vagal afferent fibres an modulate the proessing of information of the thorai spinothalami trat ells reeiving afferent input from the heart, by ativating supraspinal pathways and nulei. Contrary to the idea that ativation of vagal afferent fibres may lead to viseral pain, exept in the nek and jaw regions, the vagal afferents may serve as an important rapid signalling pathway for ommuniating the immune hanges from the periphery to the areas in the brain that respond to infetion and inflammation. Infetion and inflammation eliit the prodution of vasoative and neurohumoral ompounds. Depending on the integrity of the vagal afferent pathway, the release of inflammatory ytokines like interleukin (IL)-1, IL-6, IL-1b, and tumour nerosis fator a, trigger several systemi responses. This reation indues alterations in pain sensitivity and metabolism, hyperthermia, and inreased release of adrenoortiotropin, gluoortioids, and liver aute phase proteins. Furthermore, vagal afferent stimulation ativates the hypothalamus pituitary adrenal axis. Finally, the ativation of this vagal pathway to supraspinal strutures, suh as the hypothalamus and the amygdala, may ativate desending antinoieptive pathways that may provide projetions of a viseral organ against loal inflammatory reations. Based on this information, it is possible that vagal ativation resulting from the release of ytokines might produe the inhibition of spinothalami trat ells and spinal neurones in the thorai segments. In summary, the vagal afferent pathway to supraspinal strutures might be important for eliiting the immune responses resulting from systemi infetions and inflammation, and might not be the pathway that ontributes to the pereption of angina petoris. Angina petoris The linial manifestations of angina petoris are typially provoked through exerise and abate during rest. Usually the patient suffering from effort angina an predit the amount of physial exerise that auses his or her angina. At maximal exerise the faltering blood flow through the diseased oronaries implies a fixed narrowing (stenosis) in the oronary arteries. At rest, the anginal threshold is influened by, among other fators, emotional stress, exposure to old weather, superfluous meals, and smoking. These aspets suggest a dynami stenosis in a oronary artery. As a onsequene, the variability of the anginal threshold is determined by the interplay between the fixed and the variable obstrution in the oronary arteries. Angina petoris is not a very speifi indiator for olusive oronary disease, sine it is a relatively late, inonsistent, and non-speifi phenomenon. In ontrast, in the sequene of events resulting from myoardial ishaemia, angina petoris is a sensitive parameter. Myoardial ishaemia may our in the presene of at least 60% narrowing of the diameter of a oronary artery, while anginal omplaints may begin when the stenosis is already more than 75%. Only 75 years ago the momentary angina pain was linked to myoardial ishaemia. 5 To date, from anatomial, pathophysiologial, and neuroardiologial viewpoints, angina petoris is onsidered to be the symptomati result of ishaemi atherosleroti oronary artery disease, assoiated with an impaired residual oronary blood flow (reserve). In a patient suffering from exerise indued angina petoris this ishaemi threshold is determined by systoli blood pressure, heart rate, and ontration fore. 6 During exerise, patients with advaned CAD often experiene a rushing, onstritive, suffoating disomfort, usually in the upper substernal area, sometimes radiating to adjaent areas (predominately the left side), suh as arms, nek, throat, jaw, and teeth. The provoked viseral noieption is haraterised by its vaguely distributed, emotionally harged aspets, and the influene of emotions on the experiene of the anginal pain. The vaguely loalised and loaded noieptive information of the eliited angina petoris is onveyed by viseral afferent nerve fibres, following sensitisation of ardia (C and A delta) nerve endings. 7 Sensitisation of multireeptive nerve endings is believed to be effeted through substanes suh as adenosine and prostaglandins. The latter sensitise ardia sympatheti afferents for bradykinin. Other vasoative and neurohumoral substanes involved in ishaemi pain are endorphins, vasular intestinal protein, amino butyri aid, neuropeptide Y, and serotonin. 8 Transmitters are released by pressure (streth), infetion (irritation), nervous and hemial stimuli, and (myoardial) ishaemia. After indution of the stimulus, a neuro-hierarhi omplex of gating at multiple levels, overlapping reeptive fields, and asending and desending nervous pathways modulate the propagation of information to the ortex and hene determines the ultimate noieption. The involvement in the pereption of angina petoris of the limbi system and predominantly the (hypo)thalami area has reently been demonstrated, making use of positron emission tomography. 9 In this perspetive it is illustrative that mental stress and physial exerise indued myoardial ishaemia produes the same alterations in higher brain entres. Moreover, the hierarhial organisation of the nervous system enables it to settle with ompromised balanes and so restore the integrity of ardiomyoyte funtion. Consequently, the afferent and efferent ardia nervous system may be onsidered as a hierarhial nervous loop from whih one limb is interating with the other. In addition to this neural feedbak pathway, a (neuro)humoral iruit is suggested. In response to stress, the efferent humoral pathway indues the release of gluoortioids, noradrenaline (norepinephrine), and adrenaline (epinephrine). The humoral afferent limb has only reently been Heart: first published as 10.1136/hrt.2003.025031 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 24 November 2018 by guest. Proteted by opyright.

Criteria for hroni refratory angina petoris Debilitating angina petoris Inadequately ontrolled by mediation Results from signifiant oronary artery disease Parallelled by reversible myoardial ishaemia No options for revasularisation postulated and links the ishaemi heart to ognitive brain entres via ytokines (fig 1). 10 CHARACTERISTICS OF PATIENTS WITH (CHRONIC REFRACTORY) ANGINA PECTORIS Patients with hroni refratory angina lead severely restrited lives and perform only limited ativities. Moreover, the psyhologial stress aused by awareness of the inreased risk of a myoardial infartion often plaes an additional burden on the patient and his or her family. These patients are usually haraterised by a long history of oronary artery disease. During this part of their life, patients have therefore often experiened numerous hospital admissions, aused by an aute worsening of their oronary artery disease expressed as either a period of unstable angina or a myoardial infartion. Treatments that redue these patients angina not only improve their quality of life but will also ameliorate their psyhosoial status. In addition to antianginal mediation, they have often been treated with one or more perutaneous transluminal oronary angioplasty (PTCA) proedures or oronary artery bypass graft surgery (CABG). Most patients 227 Heart: first published as 10.1136/hrt.2003.025031 on 16 January 2004. Downloaded from http://heart.bmj.om/ Figure 1 Shemati drawing of afferent and efferent nervous (solid lines) and efferent and suggested (question mark) afferent neurohumoral (dotted lines) pathways. Heart: mehanial and hemial polymodal reeptors. Spino-thalami trats: gating and modulation. Thalamus: gating, oordination, and integration. Cerebral ortex: psyhologial influene. on 24 November 2018 by guest. Proteted by opyright.

228 suffering from hroni refratory angina petoris are relatively young, predominantly male, with a moderately hampered left ventriular ejetion fration and elevated 11 12 fibrinogen values (table 1). The inreased fibrinogen is most likely to be an epiphenomenon, related to hroni inflammation indued by oronary artery disease. However, an inreasing number of patients, surviving various ishaemi events, are suffering from hroni angina petoris, most likely as a result of sensitisation (that is, a redued pain threshold), refratory to onventional strategies. The prevalene is estimated to be 100 000 patients in the USA, with an equal number in Europe. 13 Their angina is onsidered to be refratory when, despite optimal antianginal pharmaologial treatment and the presene of persistent reversible myoardial ishaemia, revasularisation is no longer feasible. Patients suffering from angina petoris, resistant to onventional treatments, may be onsidered as survivors of their oronary artery disease. Sine they are invalided by their anginal pain, without onventional treatment options the patients have unmet medial needs. Subsequently, any additional treatment that relieves their omplaints without adversely affeting their hroni disease is worth taking into onsideration. The argument for fousing attention on improving these patients quality of life is partiular valid with respet to the prognosis of those who survive with end stage heart disease for a long period of time, as expressed in the low annual ardia mortality of about 5%. 11 TREATMENT FOR ANGINA In addition to improvement in lifestyle, the onventional way to improve myoardial ishaemia is by either reduing the oxygen demand (b blokers, alium hannel blokers) or by improving the supply (nitrates, revasularisation proedures suh as PTCA or CABG). Additive measures, suh as lipid lowering, inhibition of platelet aggregation, and interferene in the renin-angiotensin system have beome established treatments for stable angina petoris. In the vast majority of patients these strategies are suffiient to ontrol the symptoms. Adjuntive treatments for hroni refratory angina petoris If onventional treatments fail to ontrol the patient s ondition, many adjuntive therapies are available. In general, four types of additional treatment an be offered to patients with therapeutially refratory angina (fig 2). First, the appliation of additional mediation, administered either systemially suh as ordarone, helation, opioids, and (intermittent) urokinase, or loally, suh as intratheally applied anaesthetis or opioids. In general, the use of adjuntive mediation for long term treatment is withheld beause of its drawbaks (opioids), beause it is only suitable for short term appliation (intratheally applied anaesthetis), it is ostly (urokinase), or it has not proven to be effetive for this indiation (helation, ordarone). Mediations targetting inflammation and thrombosis are onsidered to be more potent options in the near future. Seond, treatments aimed at improving myoardial perfusion, by means of a rehabilitation programme or by affeting the haemodynami system. The trade-off of the benefiial effets of ardia rehabilitation programmes on ardia performane is the need for ontinuation of the programme. 14 Angina petoris may also be treated by enhaned external ounterpulsation. This method is direted at diastoli augmentation of blood flow in the oronary arteries through an inrease in aorti retrograde blood flow, indued by ompression of uffs that are wrapped around the legs. Reently, enhaned external ounterpulsation has been reported to be effetive in improving myoardial perfusion during stress in patients with hroni stable angina. 15 However, experiene is limited and the equipment ostly. Third, modulation of the nervous system. The nervous system an be modulated through spinal ord stimulation or transutaneous eletrial nerve stimulation. Neuromodulation appears to be one of the most suessful adjuntive treatments. It is a reversible therapy and has been reported to be effetive, without onealing angina petoris during an aute myoardial infartion. The benefiial effets of neuromodulation, expressed in a redution in the number and severity of anginal attaks in onjuntion with an improvement in exerise apaity and quality of life, have been reported to last for several years. Evidene that spinal ord stimulation exerts an additional anti-ishaemi effet is provided by studies on exerise testing, ambulatory ECG monitoring, positron emission tomography, and oronary flow measurements. The explanation for the redution in Table 1 Charateristis of patients (n = 517) suffering from hroni refratory angina petoris. Modified from TenVaarwerk et al. 11 Sex 71% male Age (years) 63.9 (10.1) Clinial presentation Duration of angina petoris (years) 8.1 (6.3) NYHA lass (mean) 3.5 (0.7) LVEF (40% 24% Previous myoardial infartion 66% Three vessel disease 68% PTCA 17% CABG 58% Risk fators Family CAD 61% Hypertension 39% Hyperholesterolaemia 28% Smoking 21% IDDM 14% CAD, oronary artery disease; CABG, oronary artery bypass graft surgery; IDDM, insulin dependent diabetes mellitus; LVEF, left ventriular ejetion fration; NYHA, New York Heart Assoiation funtional lass; PTCA, perutaneous transluminal oronary angioplasty. Figure 2 Shemati representation of additional therapeuti options for patients with hroni refratory angina petoris. ECCP, enhaned external ounterpulsation; SCS, spinal ord stimulation; TENS, transutaneous eletrial nerve stimulation; VEGF, vasular endothelial growth fator. Heart: first published as 10.1136/hrt.2003.025031 on 16 January 2004. 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myoardial ishaemia may be a homogenisation of the myoardial perfusion. 16 Furthermore, there is evidene that eletrial stimulation of the dorsal aspet of the spinal ord stabilises the intrinsi ardia nervous system and may therefore prevent deleterious onsequenes, suh as eletrial instability of the ventriles. 17 Finally, researh performed by Kanno and olleagues in 1999 may shed new insights into the influene of eletrial stimulation on the onentration of vasular endothelial growth fator (VEGF). From his investigations on low intensity (10% of ontration threshold) eletrial stimulation in ishaemi hind paw musles of rabbits and in musle ells in vitro it may be onluded that VEGF mrna onentration after stimulation is inreased signifiantly. Denervation of the heart by endosopi transthorai sympathetomy has also been reported in a very limited number of publiations over the last deade. The drawbak of these destrutive experimental treatments is a relatively high mortality and morbidity, ranging from 5 10%. 18 Arbitrarily, these latter adjuntive treatments ould also be lassified into the next ategory. Fourth, treatments aimed at vessel formation through upregulation of vasular endothelial growth fators induing angiogenesis, making use of stem ells, or applying either transmyoardial (TMR) or perutaneous laser (PMR). Restoration of funtion by means of angiogenesis is a stepwise experimental proedure, best studied by making use of gene therapy. Gene therapy an be applied by diret intramyoardial injetion of naked DNA enoding for VEGF, a heparin binding glyoprotein, as well as adenoviral transfetion with VEGF. Regulation of VEGF mainly takes plae via oxygenation of tissues. Ishaemia enhanes both the expression and prodution of VEGF. Furthermore, sine an inreased onentration of VEGF mrna has been demonstrated in ishaemi tissues, this suggests a negative feedbak system. When oxygen onentration in the tissues inreases, VEGF gets down regulated. At the onset of the angiogenesis proess, endothelial ells produe metalloproteinases to digest the basement membrane. Next, the endothelial ells may disonnet from the basement membrane, and are able to migrate, proliferate, and form a network of endothelial tubes. To beome funtionally important the vessels then need to mature. During the following arteriogenesis, nasent vessels beome extensively overed by a musular oat reating blood vessels with visoelasti and vasomotor properties. 19 Studies on gene therapy have demonstrated a remarkable improvement in flow to ishaemi areas in peripheral arteries as well as in the heart. 20 Although the linial results are enouraging, there is a need for further validation in plaebo ontrolled trials. With Ten harateristis of patients with hroni refratory angina petoris, 70 years old Predominantly male Long term ( 10 years) oronary artery disease Three vessel disease Previous myoardial infartion(s) Previous revasularisation proedure(s) Maintenane of left ventriular funtion No serious arrhythmias Annual ardia mortality,5% Raised fibrinogen values respet to angiogenesis most onerns relate to the vehile, usually a genetially manipulated virus, delivering the growth fator. Though the long term effets of these geneti therapies are not yet known, the vehile issue should be of minor onern in the ase of plasmid based delivery. In onlusion, gene therapy indued new blood vessel formation, making use of angiogeneti growth fators, is a reent and promising development. TMR and PMR are meant to improve the flow through the myoardium by hannelling with laser beams. Mirhoseini was the first to advoate diret laser therapy of the myoardium as a treatment for refratory angina petoris, in 1981. The idea initially was to reate transmural hannels from the left ventriular avity into the myoardial musle to improve myoardial perfusion. Although some animal studies have suggested pateny of lasered hannels, most reent studies and neropsy reports showed olusion of the lasered hannels within one day, making neo- revasularisation as a mehanism of ation unlikely. Also denervation of the heart or laser indued angiogenesis with subsequent ollateralisation ausing improvement of perfusion is not proven. Initially the myoardium was lasered from the epiardial side during heart surgery, both as an adjunt to bypass surgery and as a stand alone proedure. Early studies showed a high postoperative mortality. Randomised ontrolled studies omparing laser therapy with medial treatment reported inonsistent findings. The majority showed a redution of anginal omplaints, some an improvement in exerise apaity, and only one study demonstrated an improved perfusion. Developments in atheter based tehnology made it possible to deliver the laser energy from the endoardial side. Preliminary data show that effiay is in the same range as surgial based laser therapy. However, in view of the unknown underlying mehanism of ation, to date laser therapy is not reommended for this subset of patients. Finally, heart transplantation is not onsidered a feasible treatment for this group of patients. Some of the disussed adjuvant treatments have lass 2A or lass 2B indiations, aording to the reent Amerian Heart Assoiation/Amerian College of Cardiology guidelines. 21 CONCLUSIONS The numbers of patients suffering from angina petoris hronially resistant to onventional treatments are inreasing. Patients with hroni refratory angina differ from the ordinary angina patient in three ways: first, patients with hroni refratory angina petoris maintain their left ventriular funtion despite severe three vessel disease; seond, they do not experiene severe arrhythmias and therefore their mortality is only about 5%; and third, their angina is debilitating. New and often promising treatments for this ondition are worth taking into onsideration.... Authors affiliations M J L DeJongste, R A Tio, Department of Cardiology, Thoraxenter, University Hospital of Groningen, The Netherlands R D Foreman, Department of Physiology, OUHSC, Oklahoma City, Oklahoma, USA REFERENCES 1 Maseri A. Chroni stable angina. In: Maseri I, ed. Ishemi heart disease. New York: Churhill Livingston, 1995:71 103, 477 505. Exellent book on the bakground of myoardial ishaemia 229 Heart: first published as 10.1136/hrt.2003.025031 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 24 November 2018 by guest. 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230 2 Sylvén C. Neurophysiologial aspets of angina petoris. Z Kardiol 1997;86(suppl 1):95 105. 3 Jones NL, Killian KJ. Exerise limitation in health and disease. N Engl J Med 2000;343:633 41. 4 Tomai F. Phentolamine prevents adaptation to ishemia during oronary angioplasty: role of alpha-adrenergi reeptors in ishemi preonditioning. Cirulation 1997;96:2171 7. 5 Keefer CS, Resnik WH. Angina petoris; a syndrome aused by anoxemia of the myoardium. Arh Intern Med 1928;41:769. 6 Braunwald E. Personal refletions on efforts to redue ishemi myoardial damage. Cardiovas Res 2002;56:332 8. One of the world s leading ardiologists disusses his more than 50 years of researh experiene and the positive results ahieved with nerve stimulation for severe angina petoris in 1967. 7 Longhurst JC, Tjen-A-Looi SC, Fu LW. Cardia sympatheti afferent ativation provoked by myoardial ishemia and reperfusion. Mehanisms and reflexes. Ann NY Aad Si 2001;940:74 95. 8 Gui J-G. Spinal ord stimulation in neuropathy. Experimental studies of neurohemistry and behaviour. Stokholm, Sweden: Thesis Karolinska Institute, 1999. 9 Rosen SD, Paulesu E, Frith CD, et al. Central nervous pathways mediating angina petoris. Lanet 1994;344:147 50. The first study in man of the entral nervous pathways of angina petoris, making use of positron emission tomography, suggesting the thalamus ats as a gate for pain signals to the brain. 10 TerHorst GJ, Nagel JG, DeJongste MJL, et al. Seletive blood brain barrier dysfuntion after intravenous injetions of rtnfa in the rat. In: Teelken A, Korf J, eds. Neurohemistry and neuroimmunology of EAE; impliations for therapy of MS. New York: Plenum Press, 1997:141 6. 11 TenVaarwerk IA, Jessurun GA, DeJongste MJ, et al. Clinial outome of patients treated with spinal ord stimulation for therapeutially refratory angina petoris. The working group on neuroardiology. Heart 1999;82:82 8. Largest linial experiene (n = 517) with spinal ord stimulation in relation to baseline harateristis. 12 Shoebel FC, Frazier OH, Jessurun GAJ, et al. Refratory angina petoris in end-stage oronary artery disease evolving therapeuti onepts. Am Heart J 1997;134:587 602. 13 Mannheimer C, Camii P, Chester M, et al. The problem of hroni refratory angina. Report from the ESC joint study group on the treatment of refratory angina. Eur Heart J 2002;23:355 70. This paper is a landmark publiation on hroni refratory angina, disussing different adjuntive treatments. 14 Linxue L, Nohara R, Makita S, et al. Effet of long-term exerise training on regional myoardial perfusion hanges in patients with oronary artery disease. Jpn Cir J 1999;63:73 8. 15 Stys TP, Lawson WE, Hui JC, et al. Effets of enhaned external ounterpulsation on stress radionulide oronary perfusion and exerise apaity in hroni stable angina petoris. Am J Cardiol 2002;89:822 4. 16 DeJongste MJL, Staal MJ. Spinal ord stimulation for hroni refratory angina petoris. XXI Congress of the European Soiety of Cardiology. Navaro-Lopez F, ed. Monduzzi Editore Int. Bologna (Italy): Proeedings Division, 1999:337 41. 17 Foreman RD, Linderoth B, Ardell JL, et al. Modulation of intrinsi ardia neurons by spinal ord stimulation: impliations for its therapeuti use in angina petoris. Cardiovas Res 2000;47:367 75. 18 Wettervi C, Claes G, Drott C, et al. Endosopi transthorai sympathetomy for severe angina. Lanet 1995;345:97 8. 19 Carmeliet P. Mehanisms of arteriogenesis and arteriogenesis. Nature Med 2000;6:389 95. Review disussing ellular and moleular mehanisms underlying the formation of angiogenesis and arteriogenesis during physiologial and pathologial onditions, and some optional therapeuti appliations. 20 Tio RA, Tkebuhava T, Sheuermann TH, et al. Intramyoardial gene therapy with naked DNA enoding vasular endothelial growth fator improves ollateral flow to ishemi myoardium. Hum Gene Ther 1999;10:2953 60. 21 Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with hroni stable angina summary artile; a report of the Amerian College of Cardiology/Amerian Heart Assoiation task fore on pratie guidelines (ommitte on the management of patients with hroni stable angina). Cirulation 2003;107:149 58. Heart: first published as 10.1136/hrt.2003.025031 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 24 November 2018 by guest. Proteted by opyright.