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The European Society of Cardiology

Therapeutic options for patients with chronic myocardial ischaemia

P.W Serruys* and J Aoki

Department of Interventional Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands

* P.W. Serruys, Department of Interventional Cardiology, Thoraxcenter Bd 406, Dr. Molewaterplein 40, Erasmus MC, NL-3015GD Rotterdam, The Netherlands. Tel.: +31-10-4635-260; fax: +31-10-4369-154
p.w.j.c.serruys{at}erasmusmc.nl

Abstract

Coronary heart disease (CHD) is a leading cause of death and disability worldwide. Chronic myocardial ischaemia resulting from CHD can cause stable angina and interfere with ordinary activities. Numerous approaches for reducing myocardial ischaemia are currently available. These include lifestyle changes such as weight reduction, exercise, smoking cessation and reduced consumption of salt and fat; pharmacological approaches such as use of anti-platelet agents, statins, angiotensin converting enzyme inhibitors, ß-blockers, calcium channel blockers and nitrates; surgical revascularization approaches such as coronary artery bypass grafting and percutaneous methods (balloon angioplasty, bare-metal stents, drug eluting stents). Alternative methods for reducing anginal pain such as external enhanced counterpulsation and spinal cord stimulation are also available. Despite this wide range of choices, patients with ischaemic heart disease usually require a combination of these therapies, and may continue to experience symptoms. While traditional therapies continue to be improved, strategies to increase myocardial circulation by stimulating formation of collateral vessels around obstructed coronary arteries are also in development. These approaches include therapy with recombinant growth factor proteins, transfer of growth factor genes and stem cell therapy. It is hoped that at least one of these approaches will safely and effectively reduce myocardial ischaemia, providing a new option for patients with CHD.

Key Words: Coronary heart disease • Myocardial ischaemia • Chronic stable angina • Prevention • Treatment

Introduction

Atherosclerosis, which includes coronary heart disease (CHD), heart failure, stroke and peripheral arterial disease, is one of the leading causes of death worldwide, accounting for 17 million deaths annually.1 Coronary heart disease is an important contributor to this statistic, resulting in approximately 20% of all deaths throughout the world (Fig. 1). In 2001, there were 7.1 million deaths from CHD and this figure is expected to reach 11.1 million in 2020.1



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  		Fig. 1 CHD causes approximately 20% of deaths each year in many different countries of the world. Reproduced with permission www.americanheart.org © 2004, American Heart Association.1

 
Chronic myocardial ischaemia, or inadequate provision of oxygen to the heart, is a common and disabling consequence of CHD. CHD results from atherosclerosis, in which plaques consisting of inflammatory cells, smooth muscle cells, lipids and fibrous tissue develop within the arterial wall.2 These plaques can reduce the flow of oxygenated blood, either by gradually narrowing the vessel lumen or by rupturing and stimulating thrombosis that blocks the artery. Atherosclerosis affects the circulation in both the coronary arteries and the microcirculation: blood flow in microvessels depends on adequate flow in the larger vessels and may be inhibited by vasoconstriction, thrombosis or microemboli.3,4 Insufficient coronary perfusion is associated with major adverse cardiovascular events including myocardial infarction (MI) and sudden death (Fig. 2).5



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  		Fig. 2 Severe and widespread hypoperfusion of the heart is associated with a high risk of cardiovascular events that can result in disability or death. Reprinted from J Am Coll Cardiol vol. 7 Ladenheim ML, Pollock BH, Rozanki A et al. Extent and severity of myocardial hypoperfusion as predictors of prognosis in patients with suspected coronary artery disease, 464–471 (1986), with permission from the American College of Cadiology Foundation.5

 
One of the syndromes resulting from myocardial ischaemia is chronic stable angina. These patients experience discomfort in the chest, jaw, shoulder, back or arm that is aggravated by exertion or emotional stress and relieved by nitroglycerin.6 Their ability to work and perform the activities of daily life may be severely limited.

A variety of treatment approaches have been developed or are currently in development to treat chronic stable angina, including lifestyle changes, nutritional supplements, drug therapies, surgical revascularization, device-based alternative therapies and angiogenic therapies. Because atherosclerosis is progressive, most current therapies are effective in a limited patient population, or for a limited period of time. Approaches are often used sequentially or in combination to achieve the optimal outcome for patients with myocardial ischaemia;6 the purpose of this publication is briefly to summarize the most common approaches.

Lifestyle modifications

Lifestyle changes to control the atherosclerosis causing CHD are often the first approach to stable angina. Most of these interventions are directed at reducing plasma cholesterol or treating the risk factors constituting the metabolic syndrome, which include abdominal obesity, fasting triglycerides >150 mg/dL, low high density lipoprotein (HDL) cholesterol, blood pressure >135/85 mmHg and fasting glucose >110 mg/dL.7 Lifestyle recommendations include reducing body weight, reducing consumption of cholesterol and fats, lowering salt intake and increasing exercise levels. Smoking cessation is also considered important for reducing the risk of cardiovascular events.6 The efficacies of these interventions have been studied in numerous clinical trials.

Dietary interventions reducing salt, cholesterol or fat intake have been shown to reduce surrogate markers of cardiovascular risk such as blood pressure or total and low density lipoprotein (LDL) cholesterol levels, but have not been shown definitively to reduce cardiovascular events.8 The benefits of reducing or modifying dietary fats on cardiovascular morbidity and mortality were assessed in 27 randomized trials, which were included in a meta-analysis.9 Although these trials in composite showed no significant effect on total mortality or protection from cardiovascular events, the investigators reported a small but potentially important reduction in cardiovascular risk in trials longer than 2 years.9 Thus, while benefit is possible, the evidence of benefit from dietary interventions is not as strong as the evidence for most drug therapies.8

Regular exercise has also been shown to have positive effects on cardiovascular risk factors by increasing exercise tolerance, HDL cholesterol levels and insulin sensitivity and by reducing body weight, blood pressure and LDL cholesterol levels.10 In addition, exercise reduces vasoconstriction and improves coronary perfusion.11 Interestingly, it is difficult to demonstrate that exercise directly reduces cardiovascular events as exercise programmes are usually part of a multifactorial intervention.6 Nevertheless, the evidence that interventions including exercise are beneficial is sufficiently strong that guidelines on the management of stable angina recommend at least 30–60 min of exercise 3–4 days a week (walking, jogging, cycling or other aerobic activity), and optimally every day.6

The benefits of smoking cessation are less controversial than the benefits of diet and exercise. Three randomized smoking cessation trials performed in a primary prevention setting demonstrated a reduction of 7–47% in cardiac event rates in patients who successfully stopped smoking compared with those who did not.12–14

Nutritional supplements

Several vitamin preparations have been proposed to prevent atherosclerosis. One possible regimen is folic acid to increase homocysteine concentrations, and another is antioxidants such as vitamins C and E to reduce lipid oxidation in atherosclerotic plaques. However, recent outcome trials have not shown a significant reduction in cardiovascular events with 2 years of folic acid therapy (0.5 mg/day) or 5 years of therapy with antioxidants (600 mg vitamin E, 250 mg vitamin C and 20 mg ß-carotene per day).15,16 Thus, these interventions are not recommended to prevent or treat cardiovascular disease.6

Hormone replacement therapy

In the past few decades, it has been common practice to prescribe post-menopausal hormones to prevent CHD, possibly because young women with normal hormonal levels have a low incidence of CHD.17 However, a series of randomized controlled trials demonstrated that hormone replacement therapy in post-menopausal women has no benefit on either primary or secondary prevention of heart disease.17 (Table 1). This therapy is, therefore, not recommended to prevent myocardial ischaemia.6


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  		Table 1 Randomized, controlled trials of hormone replacement therapy to prevent initial or recurrent cardiovascular events

 
Pharmacological therapies

Numerous pharmacological interventions have been carefully tested and are available for the prevention and treatment of myocardial ischaemia. These include anti-platelet agents, statins, angiotensin converting enzyme (ACE)-inhibitors, ß-adrenergic receptor blockers, calcium antagonists and nitrates.

Anti-platelet agents
Anti-platelet agents including aspirin, clopidogrel and ximelagatran diminish platelet aggregation and adhesion, reducing the incidence of myocardial ischaemia caused by thrombosis. Use of aspirin (75–325 mg/day) has been associated with a 32% reduction in the risk of a first myocardial infarction (MI) in an analysis of five large trials including 55,580 participants.18 Similarly, a meta-analysis of studies including about 70,000 patients with an established cardiovascular disease such as stable angina indicated that use of aspirin reduced the risk of non-fatal MI and vascular death by approximately one-third.19 Consequently, aspirin is recommended for all patients with chronic myocardial ischaemia.6

Clopidogrel is an anti-platelet agent that can be given in addition to aspirin to increase the extent of platelet inhibition. In the CURE study of patients with acute coronary syndromes but no ST-segment elevation, a composite of death from cardiovascular causes, non-fatal MI or stroke was reduced by 20% in patients given clopidogrel (75 mg/day after a loading dose of 300 mg).20 The percentage of patients with refractory or severe ischaemia was also reduced by 7%.20 The primary adverse event observed was major bleeding (3.7% in the clopidogrel group versus 2.7% in the placebo group).20 Clopidogrel is currently recommended only for patients with chronic stable angina who are unable to take aspirin;6 however, it may have a future role in the prevention of myocardial ischaemia.

Ximelagatran is an oral direct thrombin inhibitor that prevents thrombin activation of platelets and is an anticoagulant. In the ESTEEM trial, ximelagatran and aspirin were shown to be more effective than aspirin alone in preventing major cardiovascular events in patients who had had a recent MI. This treatment prevented the composite endpoint of death, non-fatal MI and severe recurrent ischaemia with 3.6% absolute and 24% relative reduction in risk over the 6-month treatment period.21 Thus, the ESTEEM data support the benefit of preventing thrombosis in patients at risk for acute coronary syndromes.

Statins
Statins, which inhibit the production of specific enzymes used to produce cholesterol,2 are particularly effective at lowering levels of LDL cholesterol and, to a lesser degree, triglycerides. They are also believed to have a plaque stabilizing effect that prevents plaque rupture and resultant thrombosis, and may enhance coronary blood flow.2 Pravastatin both increased myocardial perfusion and reduced symptoms of angina compared with placebo in the REGRESS trial of 69 patients who were followed for 2 years.22 Most importantly, large, long-term statin trials including 64,736 patients found a 27% decrease in CHD events, and a 14% decrease in all-cause mortality with consistent statin use.23 It is recommended that all patients with chronic myocardial ischaemia and LDL cholesterol >=100 mg/dL receive this therapy.6

ACE-inhibitors
ACE-inhibitors are believed to be vasoprotective, improving dilation of the vessels while preventing thrombosis. In high-risk patients with CHD, stroke, peripheral vascular disease or diabetes and at least one additional risk factor (hypertension, increased total cholesterol, low HDL, smoking or impaired renal function), ramipril decreased the risk of MI, stroke or death from cardiovascular causes by 22%.24 The individual endpoints of death from cardiovascular causes, MI, stroke, need for surgical revascularization, heart failure and worsening angina were also significantly less common in patients given ramipril () compared with those given placebo ().24 The only adverse event associated with greater discontinuation of therapy in the ramipril group than in the placebo-group was cough.24 In the EUROPA study, perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease.25 Based on these results, ACE inhibitors are recommended for patients with known CAD, including those with myocardial ischaemia.6

ß-Adrenergic receptor blockers
ß-Adrenergic receptor blockers (ß-blockers) reduce myocardial oxygen demand by decreasing heart rate, pressure and contractility. They assist with the management of both symptomatic and asymptomatic ischaemic episodes.6 Mortality is also reduced with ß-blocker therapy in patients with recent MI or hypertension, and possibly in other patient populations.6 However, some patients do not tolerate this therapy well and the most common side-effects include fatigue, inability to exercise, insomnia, nightmares, claudication and impotence.6 ß-Blockers are recommended in patients with myocardial ischaemia but without contraindications such as severe bradycardia, a pre-existing severe atrio-ventricular block or left ventricular failure.6

Calcium antagonists
Calcium antagonists inhibit channel-mediated calcium fluxes that increase smooth muscle contractility. Beneficial effects of calcium antagonists include dilation of the epicardial coronary arteries, and reduction of the myocardial oxygen requirement.6 Relief of symptoms is generally observed, however, short-acting dihydropyridine calcium antagonists may enhance the risk of adverse cardiac events, although long-acting or slow-release calcium antagonists do not.6 The most serious side-effect of calcium antagonists is worsening of heart failure, but hypotension and depression of cardiac function may also be observed. Symptoms such as peripheral oedema, constipation, headache, flushing and dizziness may also occur and be poorly tolerated.6 Calcium antagonists are recommended for reduction of symptoms when ß-blockers are contraindicated or a medication in addition to these is required to relieve angina.6

Nitrates
Nitrates such as nitroglycerin are vasodilators that reduce the requirement of the myocardium for oxygen and improve myocardial perfusion.6 Nitroglycerin has also been shown to inhibit thrombus formation in patients with stable angina.26 Although short-term use of nitrates is effective, long-term use can result in the development of tolerance;6 headaches may also be a concern. Intermittent use of sublingual nitroglycerin or nitroglycerin spray is, nevertheless, recommended for the immediate relief of angina.6

Other pharmacological therapies
Other therapies in development for the management of the patient with myocardial ischaemia include: nicorandil, a potassium channel activator with properties similar to those of nitrates; ivabradine, an inhibitor of the pacemaker current; fasudil, a rho-kinase inhibitor that acts as a vasodilator; and agents such as trimetazidine and ranolazine that affect cardiovascular metabolism.6 Ongoing clinical trials will define the benefits of these interventions for patients with myocardial ischaemia.

Surgical revascularization for myocardial ischaemia

Surgical revascularization to replace or re-open atherosclerotic vessels may be indicated if medical therapy has not relieved disabling anginal symptoms, or clinical characteristics suggest severe CHD. Coronary angiography is used to determine the location of stenoses and the number of vessels involved, which may determine the type of procedure performed.

Bypass procedures
Traditional coronary artery bypass grafting (CABG) is generally performed in patients who are at high risk of death without surgery. These patients usually have significant left main coronary disease or 3-vessel disease.6 The CABG procedure involves sternotomy, use of cardiopulmonary bypass life support during surgery and harvesting of vein or arterial grafts (preferably the latter) for transfer. An advantage of this process is that an extensively diseased vessel is removed and replaced with healthier tissue, increasing perfusion while decreasing the number of atherosclerotic lesions in the coronary vasculature. Both symptoms and mortality are decreased. A meta-analysis of trials including 2649 patients randomized to medical therapy or to CABG demonstrated a 39% decrease in mortality compared to the medically treated group.27 The results of a recent study in 305 patients >75 years of age with chronic stable angina who were randomized to CABG or medical therapy showed a 61% decrease in major cardiac events and angina over 6 months.28 However, the short-term mortality and morbidity of CABG are significant disadvantages. Overall mortality from CABG in a national database was 2.9%,29 although operative mortality in octagenarians was 15.9%.30 Possible complications include arrhythmias, low cardiac output, need for ventilation >24 h, pulmonary complications, infection and renal complications. In high-risk patients, these complications can be present in >10% of cases.29

Strategies are in development to improve the safety of CABG. Several recent retrospective studies have shown that CABG without the cardiopulmonary bypass technique (off-pump CABG or OPCABG) significantly reduces mortality and most complications, although surgery on a beating heart requires greater skill.29,30

Percutaneous approaches that use the adjacent venous circulation to bypass an obstructed artery are being tested (Fig. 3). In percutaneous in situ coronary venous arterialization (PICVA), a coronary artery is connected to the adjacent vein at one site upstream from the lesion, directing oxygenated blood flow into the vein. The oxygenated blood then travels through the venous system in the reverse direction to perfuse the myocardium.31 In a percutaneous in situ coronary artery bypass (PICAB), two channels are created between the coronary artery and the adjacent vein, one upstream and the other downstream from the lesion. The blood enters the upstream channel, flows through the isolated vein to bypass the lesion, and re-enters the healthy segments of the artery through the downstream channel.31 A single patient has been reported to be pain free after PICVA; however, difficulties crossing into the venous circulation have been encountered in other patients.31



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  		Fig. 3 Percutaneous methods using the adjacent coronary vein to bypass an obstructed coronary artery. (a) Percutaneous in situ coronary venous arterialization (PICVA). (b) Percutaneous in situ coronary arterial bypass (PICAB). Reproduced with permission from Oesterle SM, Reifart N, Hauptmann E, et al. Percutaneous in situ coronary venous arterialization. Circulation 2001;103:2539–43.31

 
An alternative approach, also performed via sternotomy, is a ventricle to coronary artery bypass (VCAB). In this procedure, a stent-based device (VSTENT) is used to create a conduit between the left ventricle and the left coronary artery, thereby increasing flow in the coronary artery.32 The advantage of this approach is that no grafting is necessary and it can be performed rapidly. Research into both of these techniques is very preliminary.

Trials determining the incidence of adverse coronary events including death will be needed before less-invasive approaches to CABG are recommended for patients with chronic stable angina.6

Percutaneous intervention
The goal of most percutaneous procedures is to restore flow in the existing artery rather than to establish an alternative route of circulation. These techniques are evolving rapidly, and may eventually replace bypass procedures.

Percutaneous coronary intervention (PCI) is most effective when discrete rather than diffuse lesions are present.6 Percutaneous methods have included balloon angioplasty, atherectomies to remove atherosclerotic material and metal intracoronary stenting to structurally maintain the lumen diameter. Within the past decade, stenting has become the intervention of choice, and a wide variety of stents are now available.33 To date, PCI with stenting is highly effective at reducing the symptoms of chronic stable angina associated with specific blockages, but is not proven to reduce mortality.6 In a comparison of stenting and CABG in patients eligible for either procedure, event-free survival was 14% lower in patients given a stent, primarily because of greater need for subsequent revascularizations.34

Historically, the primary concern with stenting has been restenosis, which reoccludes the artery, reduces clinical benefit and requires reintervention. Restenosis has been associated with diabetes, small vessels, long lesions and lesions at bifurcations.33 However, the development of drug eluting stents (DES) is addressing many of these problems, markedly reducing the incidence of restenosis.35 The issues remaining are less serious, and include incomplete apposition of the stent with the vessel wall, potential aneurysm, restenosis around the stent and the possibility of delayed restenosis. Increased in-stent thrombosis was not observed in clinical trials in which patients were given clopidogrel as well as aspirin for up to 3 months.36,37

The RAVEL trial of 238 patients at 19 medical centres was the first to show marked benefit of the sirolimus-eluting stent (SES) in reducing the need for repeat revascularization.36 At 1 year after implantation, the overall rate of major cardiac events was 5.8% in the SES group and 28.8% in the standard stent group.36 No patients in the SES group had restenosis >50%, compared to 26.6% in the standard stent group.36

In the SIRIUS trial of 1058 patients, failure of the target vessel was compared in patients receiving bare metal (standard) stents versus those receiving a SES at 270 days after intervention. The results showed a marked increase in cardiovascular event-free survival in patients given a SES, driven primarily by a reduced need for revascularization (16.6% in the standard stent group versus 4.1% with the SES).37 (Fig. 4).



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  		Fig. 4 The efficacy of sirolimus-eluting stents in preventing events including myocardial infarction, death and revascularization in the SIRIUS trial. Moses JW, Leon MB, Popma JJ et al. Sirolimus eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. Copyright © 2003 Massachusetts Medical Society. All rights reserved.37

 
Since April 2002, use of a DES has been the default strategy for all patients undergoing PCI at the Thoraxcenter in Rotterdam. As of September 2003, 1461 patients were given DES, including patients who would not have been eligible in the original SIRIUS trial, such as those with multi-vessel disease, acute MI or lesions at bifurcations. A 42% decrease in the combined endpoint of death, MI and total vessel revascularization compared with historical trials has been observed in actual practice to date. This and other registry studies are ongoing.

Data from DES trials are promising, and suggest that treatment of individual lesions will have more durable benefits for patients with myocardial ischaemia. The ARTS II study is comparing the mortality benefits of revascularization with multiple SES. Stents that elute drugs such as ABT-578, dexamethasone, oestrogen, everolimus, paclitaxel, tacrolimus or trapidil are also in development.

Alternative procedures

Some patients continue to experience severe symptoms of myocardial ischaemia after optimal medical therapy and one or more revascularization procedures. Others are not eligible for the procedure because of unfavourable anatomy, or a poor likelihood of success because of severe widespread disease or the likelihood of complications. Options available for these patients are described below.

Myocardial laser revascularization
Myocardial laser revascularization is believed to improve perfusion to ischaemic areas of the heart by creating a series of small channels with a laser.38 The two major approaches to laser revascularization include transmyocardial laser revascularization (TMR), which requires a thoracotomy, and percutaneous myocardial laser revascularization (PMR). Since the created channels have been found to fill with necrotic and inflammatory debris shortly after the procedure, the mechanisms of action proposed for this procedure include laser-induced denervation of the myocardium, which reduces pain, or laser-induced angiogenesis. Since no increase in myocardial perfusion has been observed in multiple trials, the former mechanism is more likely.38 Although decreased angina has been observed after TMR in randomized clinical trials including 937 patients,38 procedure-related complications such as arrhythmias, pericardial effusion and tamponade were observed in up to one-third of patients.38 The use of PMR was hoped to reduce such complications; however, the efficacy of PMR has not been demonstrated convincingly (Table 2). The positive results of an unblinded trial suggest that a significant placebo effect is possible.38 Thus, although TMR is recommended as an alternative therapy for no-option patients,6 further research is needed to support the benefits of myocardial laser revascularization.


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  		Table 2 Results of randomized, blinded, controlled trials testing the efficacy of percutaneous myocardial laser revascularization (PMR) in patients with chronic stable angina

 
Enhanced external counter pulsation
Enhanced external counterpulsation (EECP) is a non-invasive approach for increasing blood flow to the heart in patients with myocardial ischaemia. Three pairs of pneumatic cuffs are wrapped around the calves, and lower and upper thighs of the patient. During early diastole, these cuffs are inflated sequentially from distal to proximal, resulting in a milking effect of blood from the lower extremities. At onset of systole, all cuffs are deflated, resulting in acute afterload reduction.39 Usually 1 hour of treatment per day, 5 days per week for 7 weeks (35 h) is prescribed. Treatment with EECP has been shown to increase central aortic and intracoronary diastolic pressure and intracoronary blood flow velocity.40 Possible mechanisms for the benefits of EECP include opening pre-existing collateral arteries, increasing vasodilation and stimulating collateral formation.39

The international EECP patient registry (IEPR) has demonstrated reductions in the symptoms of angina and need for nitroglycerin in most patients given EECP therapy, including patients with diabetes, 69% of whom experienced less angina.41,42 However, there are concerns that this improvement is associated with a placebo effect. The only sham-controlled trial, MUST-EECP, in 139 patients with angina did not show an improvement in exercise duration and trended towards a decrease in angina, although time to ST-segment depression was improved by about 50 s.43 Adverse experiences associated with EECP include skin abrasions, bruising, and blistering and pain in the legs and back.43 Prescription of EECP is recommended for patients refractory to medical therapy who are not candidates for percutaneous intervention or surgical revascularization.6

Spinal cord stimulation
Low-voltage electric stimulation of the spinal cord can be used to inhibit the pain of angina. A small programmable pulse generator is implanted beneath the skin, and the stimulating electrode is placed in the dorsal epidural space, usually at the C7-T1 level. Small, open-label trials with spinal cord stimulation (SCS) have shown improvements in exercise duration, time to angina and perceived quality of life.6 However, a placebo effect cannot be ruled out. Complications of SCS include neurological damage, electrode migration, infection and cerebrospinal leak.6 This procedure is recommended for symptomatic patients with myocardial ischaemia who have no other options. Increased collateral formation has been viewed as a potential mechanism for improving ischaemia in a number of alternative therapies such as TMR and EECP.

Therapeutic angiogenesis
Chronic imbalances of myocardial oxygen supply and demand produced by a coronary artery stenosis or occlusion have been shown to increase growth of the coronary collateral circulation. Angiogenesis and vasculogenesis are adaptive responses of the coronary collateral circulation to myocardial ischaemia.

Therapeutic angiogenesis, which involves the administration of angiogenic growth factors or cytokines to stimulate collateral formation and improve myocardial perfusion, is being tested as an alternative treatment for patients with medically intractable angina who are not candidates for conventional revascularization techniques.

Preclinical studies have established a foundation for rational development of therapeutic angiogenesis. A variety of growth factors and chemokines convincingly increase the formation of small blood vessels in mice, rats, rabbits or pigs (Table 3).44 Most clinical trials to date involve transfer of vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF). Methods for implementing therapeutic angiogenesis include protein, gene and cell delivery.


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  		Table 3 Proteins that stimulate angiogenesis in preclinical studies44

 
Protein transfer
With the advent of recombinant DNA technology, large quantities of purified proteins can be produced for therapeutic use. Advantages of locally administering purified angiogenic factors include easy dose titration, repeat administration if necessary and rapid metabolism to prevent toxicity. The primary disadvantages have been either a lack of efficacy in placebo-controlled studies or a need for administration during CABG (Table 4). Methods combining angiogenic proteins with slow-release systems are in development.


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  		Table 4 The results of controlled Phase II clinical trials testing angiogenic factors to treat CHD

 
Gene therapy
Gene therapy is an approach in which the genetic material directing production of a protein is transferred in place of the protein itself. A number of vehicles are used for transferring DNA to heart tissue, including purified DNA, DNA/lipid complexes, adeno-associated viruses and adenovirus.44 An advantage of this approach appears to be localized, sustained but not indefinite production of angiogenic factors. Apparent disadvantages are the possibilities of vector toxicity, an immune response to the gene therapy vector or inappropriately localized gene transfer resulting in angiogenesis in a tumour or the retina.

The efficacy of gene transfer approaches to therapeutic angiogenesis are now being tested in clinical trials. Early uncontrolled, open-label, clinical trials generally gave positive results, although the possibility of a placebo effect was not excluded. Controlled Phase II trials are providing positive but not definitive results (Table 4). This is promising, since the patient population being studied has failed all other therapies and is likely to be refractory to intervention. However, most of the efficacy measures studied to date are surrogate endpoints such as exercise tolerance time, angina or perfusion. While these measures are useful in suggesting clinical efficacy, hard clinical endpoints such as mortality, MI and the need for revascularization should be studied. Long-term follow-up data are also necessary.

An important observation is that the safety results of these trials indicate no major problems. Potential side-effects such as worsening of atherosclerosis, retinopathy or cancer, have not been observed in clinical trials.44

Cell therapy
Another alternative method for increasing coronary vascularization is the transplantation of stem or progenitor cells.45 These cells not only produce a variety of growth factors and cytokines, but participate structurally in the formation of new vascular tissue.45 While this approach may be the most effective, challenges will include producing reproducible and sterile cell stocks that are not rejected and maintaining cell viability within the heart. The results of uncontrolled Phase I trials with sources of progenitor cells, including whole bone marrow, peripheral stem cells and purified endothelial progenitor cells, have been positive. Phase II trials are ongoing45 and, again, the safety results of these have been encouraging.

Depending on the results of both gene transfer and cell transfer studies, a combined approach involving gene transfer before transplantation of stem cells may be required.

Conclusion

Numerous options have been developed to treat the large and increasing number of patients with myocardial ischaemia. These include lifestyle changes such as weight reduction, exercise, smoking cessation and reduced consumption of salt and fat; pharmacological approaches such as use of anti-platelet agents, statins, ACE-inhibitors, ß-blockers, calcium channel blockers and nitrates; surgical approaches to revascularization including bypass procedures (CABG, OPCABG, PICVA, PICAB); percutaneous methods for revascularization (balloon angioplasty, bare-metal stents, drug eluting stents); and alternative methods for reducing anginal pain such as EECP and SPS. Other, less successful interventions, including nutritional therapies, hormonal therapies and percutaneous myocardial revascularization, have also been tested in clinical practice.

The proliferation of these strategies, the need for multiple approaches in individual patients and the rising death rate indicate that the problem of myocardial ischaemia is not solved. Ongoing research on the use of DES, angiogenic gene therapies and stem-cell transfer may result in additional therapeutic options benefiting patients with myocardial ischaemia. The rational design of strategies increasing natural collateral formation appears possible, but the optimum approach has not yet been established.

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