Vascular growth factors and angiogenesis in cardiac surgery

Therapeutic angiogenesis, in the form of growth factor protein administration or gene therapy, has emerged as a new method of treatment for patients with severe, inoperable coronary artery disease. Improved myocardial perfusion and function after administration of angiogenic growth factors has been demonstrated in animal models of chronic myocardial ischemia. Recently, preliminary clinical trials using growth factor proteins or genes encoding these angiogenic factors have demonstrated clinical and other objective evidence of relevant angiogenesis. A recent study reported beneficial long-term effects of therapeutic angiogenesis using fibroblast growth factor (FGF)-2 protein in terms of freedom from angina and perfusion on single-photon emission computed tomographic imaging. Thus, therapeutic angiogenesis has the potential to extend treatment options to patients who are not optimal candidates for conventional methods of myocardial revascularization. However, endogenous antiangiogenic influences, intrinsic lack of response of patients with severe endothelial dysfunction, and other limitations will need to be overcome before angiogenesis becomes a standard therapy for the treatment of patients with severe coronary disease.     

Angiogenesis for the treatment of inoperable coronary disease: the future

Improved treatment options and better management of cardiovascular risk factors have resulted in improved outcomes for patients suffering from severe coronary artery disease. However, coronary artery disease may be of such a diffuse and severe manner that repeated attempts at catheter-based interventions and coronary artery bypass grafting may be unsuccessful at restoring normal myocardial blood flow. It is the goal of therapeutic angiogenesis to restore perfusion to chronically ischemic myocardium using protein growth factors, gene therapy, or, more recently, cell-based therapy, without intervening on the epicardial coronary arteries. However, angiogenesis has not yet provided significant clinical benefit and is still reserved as an experimental treatment for patients who have failed conventional therapies. Once potential endogenous inhibitors of vascular development can be modified, angiogenesis may become more useful for therapeutic purposes. It is hoped that angiogenesis for therapeutic purposes will one day effectively re-create the potent natural processes of vascularization that every human being undergoes during growth and development and become a major modality for the treatment of coronary artery disease.     

Focal angiogenic therapy for myocardial ischemia

BACKGROUND: Therapeutic angiogenesis, which involves the administration of angiogenic cytokines to stimulate collateral formation and improve myocardial perfusion, is being tested as an alternative treatment for patients with medically intractable angina who are no longer candidates for conventional revascularization techniques. METHODS: Administration of recombinant protein formulations for these growth factors and transfection of the DNA itself have proven effective in animal models. At present, transfection of the DNA (gene therapy) appears preferable in that a single administration achieves a prolonged but transient, localized exposure of the ischemic tissues to the angiogen. The important technical aspects of surgical gene therapy via a mini thoracotomy incision are described. RESULTS: Four Phase I clinical trials of angiogenic therapy recently have been reported, two involving administration of the recombinant protein combined with coronary bypass and two involving gene therapy alone. These studies have shown that this approach is relatively safe; the early evidence of efficacy is encouraging. The largest study reported six-month follow-up on 30 patients who received plasmid DNA for vascular endothelial growth factor-165 (VEGF165) and documented improvement in angina, treadmill exercise tolerance, and myocardial perfusion in the majority of patients studied. CONCLUSIONS: These preliminary results will need to be supported by randomized clinical trials in which angiogenic therapy alone is compared to standard medical therapy or a placebo. Catheter-based intramyocardial gene transfer and combined coronary arterial bypass grafting or transmyocardial laser revascularization plus gene therapy trials are also underway. If proven effective, angiogenic therapy may provide a relatively noninvasive modality for revascularization of ischemic myocardium not amenable to current techniques.     

Transmyocardial laser revascularization

It has been almost a decade since transmyocardial laser revascularization (TMR) was approved for clinical use in the United States. The safety of TMR was demonstrated initially with nonrandomized studies in which TMR was used as the only treatment for patients with severe angina. TMR efficacy was proven after multiple randomized controlled trials. These revealed significant angina relief compared to maximum medical therapy in patients with diffuse coronary disease not amenable to conventional revascularization. In light of these results, TMR has been used as an adjunct to coronary artery bypass grafting (CABG). By definition, patients treated with this combined therapy have more severe coronary disease and comorbidities that are associated with end-stage atherosclerosis. Combination CABG + TMR has resulted in symptomatic improvement without additional risk. The likely mechanism whereby TMR has provided benefit is the angiogenesis engendered by the laser-tissue interaction. Improved perfusion and concomitant improvement in myocardial function have been observed post-TMR. Additional therapies to enhance the angiogenic response include combining TMR with stem cell-based treatments, which appear to be promising future endeavors.     

Comparison of vascular endothelial growth factor and fibroblast growth factor-2 in a swine model of endothelial dysfunction.

OBJECTIVE: Growth factor based angiogenesis, with or without cell therapy, is a promising therapeutic modality for patients with coronary artery disease. We compared the relative efficacies of surgically delivered vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in a swine model of hypercholesterolemia-induced endothelial dysfunction which captures many of the pathophysiologic abnormalities of human coronary disease. METHODS: Yucatan mini-swine (20-30 kg), fed a high cholesterol diet (total 20 weeks), underwent circumflex ameroid placement to create chronic myocardial ischemia, followed three weeks later by perivascular administration of VEGF (2 microg; n=6), FGF-2 (100 microg; n=6), or placebo (n=7) in the ischemic territory. Normocholesterolemic animals (n=7) served as controls. Four weeks later, endothelial function, collateral-dependent perfusion, as well as myocardial protein and mRNA levels of angiogenic mediators were assessed. RESULTS: Endothelial dysfunction was observed in all hypercholesterolemic animals as impaired microvessel relaxation in response to adenosine diphosphate and VEGF. VEGF administration improved baseline-adjusted collateral-dependent perfusion at rest (-0.03+/-0.05 vs -0.12+/-0.04, VEGF vs placebo, p=0.09), but FGF-2 delivery caused a significantly greater improvement in perfusion compared to either group (+0.15+/-0.03, p<0.05 vs HC-placebo and HC-VEGF) at rest. Molecular analysis revealed increased eNOS expression (135%+/-8%, p=0.03 vs placebo) in all growth factor treated animals and increased expression of FGF-2 receptor, FGFR1 (65+/-26%, p=0.04 vs placebo), in FGF-2 treated animals. No significant changes were demonstrated in other angiogenic mediators including Akt, Syndecan-4. CONCLUSIONS: In the setting of hypercholesterolemic endothelial dysfunction, FGF-2 is more effective than VEGF at enhancing collateral-dependent perfusion and thus, may be a better candidate than VEGF for angiogenic therapy in patients with end-stage CAD.     

Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation?

The physiological processes of angiogenesis, vasculogenesis and arteriogenesis contribute to the growth of collateral vessels in response to obstructive arterial disease causing lower limb or myocardial ischaemia, but in clinical practice the endogenous angiogenic response is often suboptimal or impaired, e.g. by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis is an application of biotechnology to stimulate new vessel formation via local administration of pro-angiogenic growth factors in the form of recombinant protein or gene therapy, or by implantation of endothelial progenitor cells that will synthesize multiple angiogenic cytokines. Numerous experimental and clinical studies have sought to establish 'proof of concept' for therapeutic angiogenesis in PAD and myocardial ischaemia using different treatment modalities, but the results have been inconsistent. This review summarises the mechanisms of angiogenesis and the results of recent trials evaluating the efficacy and safety of different gene therapy, recombinant protein and cellular-based treatment approaches to enhance collateral vessel formation.     

Normalization of coronary microvascular reactivity and improvement in myocardial perfusion by surgical vascular endothelial growth factor therapy combined with oral supplementation of l-arginine in a porcine model of endothelial dysfunction

OBJECTIVE: Vascular endothelial growth factor acts in part through nitric oxide release, the availability of which is decreased in endothelial dysfunction associated with advanced coronary artery disease. This could explain the relatively disappointing results of vascular endothelial growth factor therapy in clinical studies compared with animal studies. We examined the influence of L-arginine supplementation to vascular endothelial growth factor therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. METHODS: Twenty-four pigs were fed either a normal (NORM, n = 8) or high-cholesterol diet with (CHOL-ARG, n = 8) or without (CHOL, n = 8) L-arginine. All pigs underwent ameroid placement on the circumflex artery and then 3 weeks later received surgical vascular endothelial growth factor treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by means of immunohistochemistry. Vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt levels were determined by means of immunoblotting. RESULTS: Pigs from the CHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. Vascular endothelial growth factor treatment was ineffective in the CHOL group (circumflex/left anterior descending coronary artery blood flow ratios: 0.95 [rest] and 0.74 [pace] before-after treatment; P < .05 compared with the NORM group). Addition of L-arginine restored the angiogenic effect of vascular endothelial growth factor (ratios: 1.13 [rest] and 1.20 [pace]; P < .05) and was associated with increased endothelial cell density, as well as vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt protein levels in the ischemic territory. CONCLUSIONS: L-Arginine supplementation can restore normal endothelium-dependent vasorelaxation and angiogenic response to vascular endothelial growth factor in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with vascular endothelial growth factor therapy for end-stage coronary artery disease.     

Adenoviral-mediated transfer of vascular endothelial growth factor 121 cDNA enhances myocardial perfusion and exercise performance in the nonischemic state

BACKGROUND: Angiogenic gene therapy has been demonstrated to enhance perfusion to ischemic tissues, but it is unknown whether the administration of angiogenic growth factors will increase blood flow to nonischemic tissues. This study investigates whether enhanced myocardial perfusion can be mediated by adenovirus-mediated transfer of vascular endothelial growth factor 121 cDNA to nonischemic myocardium. METHODS: New Zealand White rabbits received adenovirus (5 x 10(10) particle units) encoding for vascular endothelial growth factor 121 (n = 14) or a control vector without a transgene (n = 13) or saline solution (n = 9) via direct myocardial injection. Fluorescent microsphere perfusion studies and histologic analyses were performed 4 weeks later. In a parallel study, exercise treadmill testing was performed to assess the functional effects of this therapy in Sprague-Dawley rats. RESULTS: Microsphere assessment of myocardial perfusion in rabbits 4 weeks after adenovirus-encoding vascular endothelial growth factor administration was greater than that for rats injected with control vector without a transgene or saline solution (3.2 +/- 0.5 vs 2.7 +/- 0.7 and 2.4 +/- 0.4, respectively; P <.03). The endothelial cell count per high power field was increased in animals injected with adenovirus-encoding vascular endothelial growth factor versus animals injected with control vector without a transgene or saline solution (147 +/- 27 vs 123 +/- 14 and 125 +/- 16 cells, respectively), although this did not reach statistical significance (P =.12). Rats treated with adenovirus-encoding vascular endothelial growth factor also demonstrated prolonged exercise tolerance compared with rats injected with control vector without a transgene or saline solution (exhaustion time: 26 +/- 5 minutes vs 19 +/- 2 minutes and 20 +/- 3 minutes, respectively; P =.006). CONCLUSIONS: Adenovirus encoding-mediated transfer of vascular endothelial growth factor 121 induces an enhancement in regional perfusion in nonischemic myocardium that corresponds to changes in exercise tolerance. Adenovirus-encoding vascular endothelial growth factor therapy may be useful for inducing angiogenesis in the nonischemic state, such as for prophylactic therapy of early coronary artery disease.     

Effects of L-arginine on the endogenous angiogenic response in a model of hypercholesterolemia

BACKGROUND: The angiogenic properties of vascular endothelial growth factor and fibroblast growth factor-2 are mediated in part through nitric oxide release, whose availability is decreased in endothelial dysfunction associated with advanced coronary artery disease. We examined the influence of L-arginine supplementation on the endogenous angiogenic response to ischemia in a porcine model of hypercholesterolemia. METHODS: Eighteen Yucatan pigs were fed either a normal (NORM, n=6) or a high-cholesterol diet, with (CHOL-ARG, n=6) or without (CHOL, n=6) L-arginine (100 mg/kg/day), throughout the experiment. All pigs underwent ameroid constrictor placement on the circumflex artery (LCx). Seven weeks later, endothelium-dependent coronary microvascular responses to fibroblast growth factor-2 and vascular endothelial growth factor were assessed by videomicroscopy. Perfusion was assessed with radioactive microspheres; angiogenesis was evaluated by platelet-endothelial cell adhesion molecule-1 (CD-31) staining. Regional myocardial function was assessed by sonomicrometry. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase was measured by Western blot analyses. RESULTS: Pigs from the CHOL group showed significant endothelial dysfunction in the LCx territory. The dysfunction was normalized partially by L-arginine supplementation, which restored the response in the LCx territory to the level of the nonischemic anterior wall. L-arginine supplementation resulted in increases of perfusion, density of capillary endothelial, and level of endothelial nitric oxide synthase in the ischemic region. Despite these findings, no improvement in myocardial regional function was found. CONCLUSIONS: L-arginine supplementation can partially restore endothelium-dependent vasorelaxation and improve myocardial perfusion in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with growth factor therapy for end-stage coronary artery disease.     

Atorvastatin increases myocardial indices of oxidative stress in a porcine model of hypercholesterolemia and chronic ischemia

BACKGROUND/AIM: Atorvastatin has previously been shown to reduce the endogenous angiogenic response to chronic ischemia in a porcine model. One possible mechanism for this effect is reduced bioavailability of nitric oxide, a key mediator of angiogenesis, secondary to increased oxygen free radicals. We sought to determine if atorvastatin modulates oxidative stress in myocardial tissue. METHODS: Dietary induction of hypercholesterolemia was performed over 20 weeks in Yucatan swine with treated animals receiving atorvastatin 3 mg/kg/day. Chronic myocardial ischemia was induced via surgical placement of an ameroid constrictor ring around the proximal circumflex artery at age 20 weeks, followed by tissue harvest at age 27 weeks. Myocardial levels of protein, lipid, and DNA biomarkers of oxidative stress, serum levels of 8-isoprostane, nitric oxide (NO) dependent, and independent coronary microvascular reactivity, as well as isotope-labeled microsphere myocardial perfusion analysis and histologic analysis for endothelial cell density was performed. RESULTS: Atorvastatin treatment was associated with elevated levels of myocardial protein oxidation and lipid peroxidation. Conversely, serum oxidant stress biomarkers were not elevated. Atorvastatin treatment improved nitric oxide dependent and independent microvascular reactivity, and was associated with decreased perfusion in the ischemic myocardial territory. CONCLUSION: Treatment with atorvastatin was associated with increased levels of myocardial tissue protein and lipid oxidative stress biomarkers and a reduced functional endogenous angiogenic response, but improved coronary microvascular reactivity. Increased oxidative stress in tissues may play a role in the reduced angiogenic response seen with atorvastatin treatment in other studies.     

Therapeutic angiogenesis and myocardial regenerative medicine for ischemic heart disease

We have a new therapeutic modality, regenerative medicine, for patients with severe ischemic heart disease. Growth factor administration and cell transplantation are available. Therapeutic angiogenesis with bone marrow cell transplantation has been used clinically with favorable results. Basic fibroblast growth factor slow-release administration has recently started to be used clinically as another angiogenic therapy. It is more potent when combined with a donor artery and omentum (Bio-CABG). Myogenic cell transplantation is in clinical trials aimed at myocardial regeneration. However, it remains unresolved how transplanted myoblasts improve cardiac function and how we can prevent fatal arrhythmia. Many are researching cardiac stem cells and embryonic stem cells as candidates for myocardial regeneration. Recently, the paracrine effects of transplanted mesenchymal stem cells in the ischemic heart have been reported to contribute to improved cardiac function. Therefore, growth factors and cytokines may play an important role in the regeneration process induced by transplanted cells. We combined cell transplanstation with growth factor administration as well as reconstructive surgery for dilated left ventricle, which yielded excellent results. Our integrated strategy may result in the maximal benefits to patients in the future.     

基因或干细胞移植治疗缺血性冠心病:新世纪的挑战

基因和骨髓干细胞移植是治疗缺血性冠心病的一种新方法。细胞移植的新概念、新的研究方法为未来心血管疾病的治疗和研究提供了令人兴奋的可能性。新近的细胞移植合并基因治疗可能是此领域的革命性进展。实验和初步临床资料证实，基因或者骨髓干细胞移植能产生巨大的生物学效应，使心脏生成新生血管或者心肌细胞，改善心肌血液供应，增加心脏功能或者代谢功能。尽管仍有许多问题需要解决，血管内皮生长因子或者骨髓干细胞移植是安全的，特别适合那些弥漫性血管病变不宜进行外科干预或者PTCA的患者，但仍有必要设计具有机械终点及临床终点的大规模随机、双盲、安慰剂对照试验，进行深入研究。     

Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction

The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction （ED）. Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future. Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.     

Wall motion and perfusion analysis of transmyocardial laser revascularization

OBJECTIVE: Transmyocardial laser revascularization (TMLR) creates channels in the myocardium. The aim of the treatment is to relieve angina in patients with end-stage coronary artery disease. We studied the effect of TMLR on myocardial function and perfusion with the combination of cine magnetic resonance imaging (MRI) and thallium scintigraphy. DESIGN: Eight patients with severe triple-vessel coronary artery disease were studied with MRI and thallium scintigraphy before and 6 months after laser treatment. RESULTS: TMLR did not improve global left ventricular (LV) function or myocardial perfusion. However, systolic wall thickening deprived in segments with fixed perfusion defects in 6 months and laser treatment prevented this deprivation (p = 0.03). In addition single photon emission computed tomography (SPECT) imaging indicated that TMLR prevented conversion of reversible into fixed defects. CONCLUSION: In severe, progressing coronary artery disease TMLR does not improve global LV function or myocardial perfusion, but it preserves systolic wall thickening in fixed defects (scar). It also prevents changes from ischemic myocardial regions to scar.     

Effects of basic fibroblast growth factor microspheres on angiogenesis in ischemic myocardium and cardiac function: analysis with dobutamine cardiovascular magnetic resonance tagging.

OBJECTIVE: Therapeutic angiogenesis with angiogenic growth factors has described as one of the promising methods for collateral formation in the treatment of ischemic heart diseases. The purpose of this study is to assess the value of intramyocardial injection of slow-released basic fibroblast growth factor microspheres on angiogenesis and cardiac function in the early period of acute infarcted myocardium with dobutamine cardiovascular magnetic resonance tagging. METHODS: Acute myocardial infarction was made by ligation of the left anterior descending coronary artery distal to its first diagonal branch. Immediately after coronary artery occlusion, 1 ml of saline containing 100 microg of basic fibroblast growth factor microspheres was injected into peri-infarct myocardial area in the basic fibroblast growth factor group, whereas only gelatin hydrogel microspheres with 1 ml of saline was given in control dogs. Cardiac function was evaluated by cine magnetic resonance imaging. Dobutamine cardiovascular magnetic resonance was performed at rest and during low doses of dobutamine to assess regional wall motion. Immunohistochemical study with von Willebrand factor was performed to observe angiogenesis. RESULTS: Left ventricular ejection fraction improved markedly 10 and 17 days after treatment in the basic fibroblast growth factor group. The basic fibroblast growth factor group had more viable myocardium. Microvessel density was higher in the basic fibroblast growth factor group than in the control group except the first day after treatment. CONCLUSIONS: Intramyocardial administration of basic fibroblast growth factor microspheres can promote the growth of microvessels and improve left ventricular function and myocardial viability in the early period of acute myocardial infarction.     

Angiogenesis — a New Goal in Peripheral Artery Occlusive Disease Therapy

The vasculature is mostly quiescent in the normal adult, with the exception of the growth of new blood vessels during the female reproductive cycle. Recent advances in the knowledge concerning the molecular changes and the identification of genetic events in this vascular quiescence, as well as in vascular growth, has led to an increasing number of studies in which these phenomena are manipulated. Angiogenesis is the growth of new vessels from existing ones. Although new vessel formation is involved in many pathologic situations, like tumour growth, therapeutic angiogenesis has been presented as a novel method for the treatment of ischemic diseases, like peripheral arterial occlusive disease (PAOD).

In experimental studies therapeutic angiogenesis has been produced by recombinant growth-factor protein application as well as by growth factor gene therapy. Most widely studied factors belong to vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) families. Studies have also shown that, angiogenic growth factors stimulate endothelial cell migration and accelerate endothelial repair by enhancing post-injury re-endothelization. In clinical studies angiogenic therapy has been evaluated in patients with severe vascular diseases. The results have revealed that therapy is well tolerated as well as safe and that angiogenic therapy has a clear biologic effect. However, controlled studies are still needed to answer the question whether therapeutic angiogenesis offers a real clinical benefit to patients with PAOD.     

Approaches to the prevention of perioperative myocardial ischemia

Goals for the perioperative management of patients with coronary artery disease include: * Prevent increases in sympathetic nervous system activity: reduce anxiety preoperatively; prevent stress response and release of catecholamines by appropriate use of opioids or volatile anesthetics and beta-adrenoceptor antagonists; beta-blocker therapy should be initiated before and continued during and after the surgical procedure. * Decrease heart rate: reduction in heart rate increases oxygen supply to ischemic myocardium and reduces oxygen demand; the use of beta-blockers is the most effective means to reduce or attenuate deleterious increases in heart rate. * Preserve coronary perfusion pressure: decreases in diastolic arterial pressure in the presence of severe coronary artery stenoses will lead to decreases in blood flow; preservation of perfusion pressure by administration of fluid or phenylephrine or a reduction in anesthetic concentration may be critical. * Decrease myocardial contractility: reduces myocardial oxygen demand and can be accomplished with beta-adrenoceptor antagonists or volatile anesthetics. * Precondition myocardium against stunning and infarction: in the future, this may accomplished by stimulating the adenosine triphosphate- dependent potassium channel with agents such as volatile anesthetics and opioid delta1-receptor agonists.     

The effect of cardiopulmonary bypass perfusion pressure on myocardial gas tensions in the presence of coronary stenosis.

Mass spectrometry was utilized to determine myocardial gas tensions in dogs subjected to cardiopulmonary bypass. Myocardial ischemia occurred in animals with normal coronary arteries when cardiopulmonary bypass perfusion pressure fell 40 to 60 mm Hg below the mean aortic pressure measured prior to bypass. Myocardial ischemia did not occur, or could be eliminated when present, if cardiopulmonary bypass perfusion pressure was maintained near prebypass mean aortic pressure. In animals with constricted circumflex coronary arteries, the adverse effect of low perfusion pressure on myocardial metabolism during cardiopulmonary bypass was found to be more severe in areas of myocardium supplied by the stenotic coronary artery. It is concluded that maintenance of cardiopulmonary bypass perfusion pressure near the level of preoperative mean aortic pressure will help prevent myocardial ischemia during operation; particularly in patients with coronary artery disease.     

Gene-based therapeutic angiogenesis

Stimulating new blood vessel growth in ischemic hearts or limbs is a hopeful new approach for patients with advanced vascular disease. This approach is based generally upon the hypothesis that sufficient exposure of a vascular bed to an angiogenic protein will stimulate neovascularization. Most angiogenic proteins have a markedly short serum half-life. To overcome this, researchers have turned to gene therapy to ensure continuous expression of angiogenic proteins and prolonged exposure in the targeted vascular beds. This field is still evolving, and although early clinical trial results suggest angiogenic gene therapy can be successful, many questions remain. As we continue to learn more about the complex interplay and coordinated action of the various factors involved in regulating angiogenesis, it is likely that strategies for therapeutic angiogenesis will continue to change. This review addresses the current state of angiogenic gene therapy, contrasts gene therapy with angiogenic protein delivery, describes early and recent clinical trial data, and discusses potential new directions in the field.