Current clinical perspectives on myocardial angiogenesis

Currently accepted modalities of treatment for atherosclerotic coronary artery disease (CAD) include pharmacological therapy, and revascularization with either bypass surgery or percutaneous coronary intervention (PCI). Similarly, conventional treatment of congestive heart failure (HF) is limited to medical therapy, temporary assist devices and in a select few, cardiac transplantation. A significant subset of patients with severe symptomatic CAD and end stage HF is not eligible for these traditional methods of treatment. In spite of maximal medical and revascularization therapy, these patients may not get adequate symptomatic relief. After a decade of investigations, gene therapy is emerging as a promising therapeutic option for this group of patients. This review discusses myocardial angiogenesis as a therapeutic modality in these patients including therapeutic angiogenesis with growth factors and cell transplantation. (Mol Cell Biochem 264: 157–167, 2004)     

VEGF gene therapy for coronary artery disease and peripheral vascular disease

Coronary artery disease (CAD) and peripheral arterial disease (PAD) are significant medical problems worldwide. Although substantial progress has been made in prevention as well as in the treatment, particularly of CAD, there are a large number of patients, who despite maximal medical treatment have substantial symptomatology and who are not candidates for mechanical revascularization. Therapeutic angiogenesis represents a novel, conceptually appealing treatment option. Ad(GV)VEGF121.10 (BIOBYPASS) is an adenovector, carrying the transgene encoding for human vascular endothelial growth factor 121 (VEGF(121)). A number of preclinical studies have demonstrated angiogenic activity of BIOBYPASS, not only anatomically but also functionally. Phase I clinical studies have demonstrated that intramyocardial infection of BIOBYPASS in patients with severe CAD as well as intramuscular injections of BIOBYPASS in patients with severe peripheral vascular disease (PVD) was well tolerated; furthermore, these studies provided some intriguing indications of activity, which led to initiation of major randomized Phase II "proof-of-concept" studies. This paper provides a review of the rationale behind BIOBYPASS as well as a summary of pertinent preclinical and early clinical data.     

Coronary artery bypass grafting (CABG): reassessing efficacy,safety, and cost

Based on randomized clinical trials begun in the 1970s showing the superiority of coronary artery bypass grafting (CABG) to medical management for patients with coronary artery disease (CAD), CABG has been routinely used to reduce angina and improve chances of survival in patients with CAD. Since CABG became a recognized standard treatment of CAD, considerable evidence has accumulated concerning the pathogenesis of CAD; the efficacy, risks, and costs of CABG; and the effectiveness of CAD risk factor reduction. To re-evaluate efficacy, safety, and cost of CABG, a MEDLINE search was performed to locate randomized trials comparing CABG vs nonsurgical management, CAD pathogenesis studies, and articles evaluating efficacy of coronary artery risk factor reduction behaviors. The extent of revascularization with CABG bore no relationship to relief of angina or survival. Randomized CABG vs medical management studies revealed that only patients with the most advanced CAD had improved survival, and this advantage vanished after 12 years. Researchers kept little coronary risk factor reduction data in the original CABG vs medical management randomized trials. However, in the Bypass Angioplasty Revascularization Intervention (BARI) study, surgically treated patients adopted lifestyles associated with lower coronary risk significantly more than patients treated with angioplasty. Factors other than revascularization cause the improvement in angina associated with CABG. Temporary survival advantages of CAD high-risk subgroups after CABG may be better explained by risk factor reduction rather than by revascularization. Using the BARI data, including lifestyle factors, a multivariate analysis of the influences determining survival and quality-of-life end points would test this hypothesis.     

Emerging relations between infectious diseases and coronary artery disease and atherosclerosis

Cardiovascular disease is the leading cause of death in developed countries. The cause is multifactorial. A substantial proportion of patients with coronary artery disease (CAD) do not have traditional risk factors. Infectious diseases may play a role in these cases, or they may intensify the effect of other risk factors. The association of CAD and Chlamydia pneumoniae infection is firmly established, but causality is yet to be proven. The link with other infectious agents or conditions, such as cytomegalovirus, herpes simplex virus, Helicobacter pylori and periodontitis, is more controversial. Cytomegalovirus infection is more strongly linked than native CAD to coronary artery restenosis after angioplasty and to accelerated CAD after cardiac transplantation. However, new data on this topic are appearing in the literature almost every month. The potential for novel therapeutic management of cardiovascular disease and stroke is great if infection is proven to cause or accelerate CAD or atherosclerosis. However, physicians should not "jump the gun" and start using antibiotic therapy prematurely for CAD. The results of large randomized clinical trials in progress will help establish causality and the benefits of antimicrobial therapy in CAD.     

Evidence-based management of coronary artery disease in the elderly--current perspectives

Cardiovascular disease accounts for significant morbidity and mortality in the elderly. The clinical trial data available to guide therapy in this growing population subset are relatively limited. This review will focus on treatment approaches and recommendations obtained from subgroup analyses of elderly patients from major clinical trials for the management of chronic stable angina, acute coronary syndromes (unstable angina and non-ST-segment elevation myocardial infarction), and coronary revascularization. Recent advances in the treatment of stable angina have shown that use of angiotensin-converting enzyme inhibitors and lipid-lowering therapy as adjunctive measures show benefit in the elderly by reducing the occurrence of death, nonfatal myocardial infarction, and unstable angina. However, if patients experience disabling or unstable anginal symptoms despite effective medical therapy, coronary revascularization must be considered. Several clinical trials have shown a significant reduction in major adverse cardiac events when using intravenous glycoprotein receptor antagonists periprocedurally during percutaneous revascularization approaches in elderly patients with unstable angina or non-ST-segment elevation myocardial infarction, especially when these measures are performed as soon as possible. However, the success of myocardial revascularization by a percutaneous or surgical approach is highly dependent on the patient's associated comorbidities, especially in patients over age 80 years.     

血管内超声在冠状动脉疾病诊断和介入治疗中的应用

冠状动脉造影是目前公认的诊断冠状动脉病变和指导冠脉介入的金标准。然而,随着介入手术的发展,冠脉造影在评价冠脉病变方面存在的缺陷逐渐显露出来,已不能完全满足临床医生的需要。血管内超声以其优越的图像质量和空间分辨率在冠心病介入领域发挥独特的作用。作为冠脉造影的有效补充,血管内超声不仅能提供管腔和血管的直径信息,还能告知术者斑块负荷、斑块构成和血管重塑等,明确冠状动脉临界病变的性质、严重性和稳定性。此外,血管内超声还可以判断病变是否可以延迟血运重建,指导经皮冠状动脉介入的治疗策略和评估支架植入效果,有效地预防手术并发症。本文从血管内超声的概况,在冠状动脉疾病诊断和介入治疗等方面的应用进展进行了综述。     

Cardiac evaluation and risk reduction in patients undergoing major vascular operations.

Occult coronary artery disease often accompanies symptomatic peripheral vascular disease and has an important effect on survival. Most perioperative and late fatalities after peripheral vascular operations are due to cardiac causes. Noninvasive cardiac testing can identify patients at increased risk for postoperative cardiac complications, although controversy exists regarding the optimal preoperative evaluation. Risk reduction strategies for patients known to be at high risk are also controversial. Some authors advocate coronary revascularization with coronary artery bypass grafting or percutaneous transluminal coronary angioplasty before the vascular procedure. Others believe that the combined morbidity and mortality of 2 operations exceed those of a peripheral vascular operation performed with aggressive monitoring and medical therapy. Continuous electrocardiographic monitoring after an operation has identified silent myocardial ischemia as a powerful predictor of cardiac complications. Ongoing research is likely to provide insights into the pathogenesis of postoperative cardiac complications and may lead to specific therapeutic interventions. Few prospective studies have been done in this area, and the threshold for preoperative and postoperative intervention is unknown. I review the literature and present an algorithm to guide cardiac testing and risk reduction in patients undergoing elective vascular surgical procedures.     

Erythropoietin augments the efficacy of therapeutic angiogenesis induced by allogenic bone marrow stromal cells in a rat model of limb ischemia

Transplantation of adult marrow stromal cells (MSCs) has been developed as a new method of treating severe ischemia diseases by therapeutic angiogenesis. Erythropoietin (EPO) is capable of inducing angiogenesis and inhibiting MSCs apoptosis. The effect of EPO on the therapeutic potency of MSCs transplantation in a rat model of limb ischemia was investigated in the current study. The results indicate that the combined treatment with MSC transplantation and EPO infusion is superior to MSC transplantation alone in the treatment of limb ischemia. MSCs transplantation and EPO infusion could enhance the angiogenic effect of each other to achieve a better therapeutic effect. This combination therapy may become a more effective approach for ischemia diseases of the limbs.     

Protein-, gene-, and cell-based therapeutic angiogenesis for the treatment of myocardial ischemia

Therapeutic angiogenesis aims at restoring perfusion to chronically ischemic myocardial territories by using growth factors or cells, without intervening on the epicardial coronary arteries. Despite angiogenesis having received considerable scientific attention over the last decade, it has not yet been shown to provide clinical benefit and is still reserved for patients who have failed conventional therapies. Nevertheless, angiogenesis is a very potent physiologic process involved in the growth and development of every animal and human, and it is likely that its use for therapeutic purposes, once its underlying mechanistic basis is better understood, will one day become an important modality for patients with CAD and other types of organ ischemia. This review summarizes current knowledge in therapeutic angiogenesis research.     

Protein-, gene-, and cell-based therapeutic angiogenesis for the treatment of myocardial ischemia

Therapeutic angiogenesis aims at restoring perfusion to chronically ischemic myocardial territories by using growth factors or cells, without intervening on the epicardial coronary arteries. Despite angiogenesis having received considerable scientific attention over the last decade, it has not yet been shown to provide clinical benefit and is still reserved for patients who have failed conventional therapies. Nevertheless, angiogenesis is a very potent physiologic process involved in the growth and development of every animal and human, and it is likely that its use for therapeutic purposes, once its underlying mechanistic basis is better understood, will one day become an important modality for patients with CAD and other types of organ ischemia. This review summarizes current knowledge in therapeutic angiogenesis research. (Mol Cell Biochem 264: 119–131, 2004)     

Basic principles of angiogenesis for the interventional cardiologist

Despite tremendous advances in the management of coronary artery disease, there is a growing population of patients who remain symptomatic with residual myocardial ischemia. Therapeutic angiogenesis, designed to promote the development of endogenous conduits forming collateral blood vessels that serve to bypass coronary artery stenotic lesions, may constitute an alternative treatment strategy for patients with extensive tissue ischemia in whom contemporary therapies-antianginal medications, angioplasty, bypass surgery-have failed or are not feasible. Intensive investigation is now focused on methods that would have the potential to stimulate the development of collaterals in humans. In this review we summarize the physiology of angiogenesis and its role in development and adult life, its regulation, the effects of ischemia and hypoxia, the principles of gene therapy for angiogenesis, and an update on the current available trials data of angiogenic cytokines administration.     

Impact of different exercise training modalities on the coronary collateral circulation and plaque composition in patients with significant coronary artery disease (EXCITE trial): study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Exercise training (ET) in addition to optimal medical therapy (OMT) in patients with stable coronary artery disease (CAD) has been demonstrated to be superior to percutaneous coronary interventions (PCI) with respect to the composite endpoint of death, myocardial infarction, stroke, revascularization and hospitalization due to worsening of angina. One mechanism leading to this superiority discussed in the literature is the increase in coronary collateral blood flow due to ET. Until now, data demonstrating the positive effect of ET on the collateral blood flow and the functional capacity of the coronary collateral circulation are still lacking.Methods/designThe EXCITE trial is a three-armed randomized, prospective, single-center, open-label, controlled study enrolling 60 patients with stable CAD and at least one significant coronary stenosis (fractional flow reserve <=0.75). The study is designed to compare the influence and efficacy of two different 4-week ET programs [high-intensity interval trainings (IT) versus moderate-intensity exercise training (MT) in addition to OMT] versus OMT only on collateral blood flow (CBF). The primary efficacy endpoint is the change of the CBF of the target vessel after 4 weeks as assessed by coronary catheterization with a pressure wire during interruption of the antegrade flow of the target vessel by balloon occlusion. Secondary endpoints include the change in plaque composition as assessed by intravascular ultrasound (IVUS) after 4 weeks, myocardial perfusion as analyzed in MRI after 4 weeks and 12 months, peak oxygen uptake (V02 peak), change in endothelial function and biomarkers after 4 weeks, 3, 6 and 12 months. The safety endpoint addresses major adverse cardiovascular events (death from cardiovascular cause, myocardial infarction, stroke, TIA, target vessel revascularization or hospitalization) after 12 months. DISCUSSION: The trial investigates whether ET for 4 weeks increases the CBF in patients with significant CAD compared to a sedentary control group. It also examines the impact of two intensities of ET on the CBF as well as the histological plaque composition. The trial started recruitment in June 2009 and will complete recruitment until June 2012. First results are expected in December 2012 (4-week follow-up), final results (12-month long-term secondary endpoint) in December 2013.Trial registrationClinical trial registration information-URL: www.clinicaltrials.gov.Unique identifier: NCT01209637.     

A modified regimen of extracorporeal cardiac shock wave therapy for treatment of coronary artery disease

ABSTRACT: BACKGROUND: Cardiac shock wave therapy (CSWT) improves cardiac function in patients with severe coronary artery disease (CAD). We aimed to evaluate the clinical outcomes of a new CSWT treatment regimen. METHODS: The 55 patients with severe CAD were randomly divided into 3 treatment groups. The control group (n = 14) received only medical therapy. In group A (n = 20), CSWT was performed 3 times within 3 months. In group B (n = 21), patients underwent 3 CSWT sessions/week, and 9 treatment sessions were completed within 1 month. Primary outcome measurement was 6-minute walk test (6MWT). Other measurements were also evaluated. RESULTS: The 6MWT, CCS grading of angina, dosage of nitroglycerin, NYHA classification, and SAQ scores were improved in group A and B compared to control group. CONCLUSIONS: A CSWT protocol with 1 month treatment duration showed similar therapeutic efficacy compared to a protocol of 3 months duration.Clinical trial registryWe have registered on ClinicalTrials.gov, the protocol ID is CSWT IN CHINA.     

Lipid management after acute coronary syndrome

PURPOSE OF REVIEW: Despite advances in medical therapy and percutaneous revascularization, patients with acute coronary syndrome face a high risk of early, recurrent cardiovascular events. Interventions targeting atherogenic lipoproteins may favorably modify this risk. RECENT FINDINGS: Two randomized clinical trials, MIRACL and PROVE-IT, demonstrated efficacy of early, intensive statin therapy after acute coronary syndrome. Recent observational and meta-analyses corroborate the findings of these trials. The benefit of intensive statin treatment appears to apply broadly to elderly as well as younger patients, and to patients with or without diabetes or metabolic syndrome. Randomized trials demonstrating the efficacy of early, intensive statin treatment after acute coronary syndrome employed fixed statin dosages, and there does not appear to be an initial or achieved LDL-cholesterol level below which benefit is absent. As such, broad application of intensive statin therapy after acute coronary syndrome may be preferable to titration of statin dose to achieve specific LDL goals. Low HDL-cholesterol predicts risk after acute coronary syndrome; therefore, pharmacologic interventions to raise HDL concentration or mimic its function may help reduce that risk. SUMMARY: Early, intensive statin therapy is safe and effective after acute coronary syndrome. Future research will determine whether drugs that raise or mimic HDL-cholesterol are effective adjuncts to statin therapy.     

Differences in oxidative stress markers based on the aetiology of heart failure: Comparison of oxidative stress in patients with and without coronary artery disease

Abstract

Various oxidative stress markers have been measured to evaluate the status of heart failure (HF). However, the relationships between these markers and the aetiology of HF have not been fully investigated. This study compared 8-hydroxy-2′-deoxyguanosine (8-OHdG) and biopyrrins levels in patients with ischemic and non-ischemic HF. Study subjects were divided into a coronary artery disease (CAD) group (n=70), a non-CAD group (n=61) and a control group (n=33). In the CAD group, 8-OHdG and biopyrrins levels increased with the severity of the New York Heart Association (NYHA) functional class and log BNP levels correlated with 8-OHdG and biopyrrins levels. However, non-CAD patients with NYHA class III/IV had significantly lower 8-OHdG levels than CAD patients with NYHA class III/IV and the levels did not correlate with log BNP levels. In the CAD group, 8-OHdG levels reflected the severity of atherosclerosis. These results indicate that the properties of oxidative stress markers should be carefully taken into consideration for the assessment of HF status.     

Autologous bone marrow mononuclear cell therapy improves symptoms in patients with end-stage peripheral arterial disease and reduces inflammation-associated parameters

Background aimsThe purpose of this study was to evaluate the effect of autologous bone marrow mononuclear cells (BM-MNCs) on symptoms and perfusion indices in severely symptomatic patients with peripheral arterial disease (PAD) without further option for endovascular or surgical revascularization.MethodsOnly patients with severe symptomatic PAD (Fontaine class IIb-IV, Rutherford category 3–6) not amenable for revascularization were treated. Bone marrow from both cristae iliacae was harvested; MNCs were isolated by the Ficoll density-gradient method and transplanted by means of intra-arterial and intramuscular injection in the index limb. Functional (pain score, ulcer healing, maximum walking distance) and perfusion indices such as ankle-brachial-index and transcutaneous oxygen pressure were documented before and after BM-MNC therapy. Additionally, serum concentration of C-reactive protein and interleukin-6 were measured as markers of inflammation before and after BM-MNC treatment.ResultsSixteen consecutive patients (four women; mean age, 63.0 ± 13 years) were treated with a mean dose of 4.2 ± 2.2 × 10⁸ BM-MNCs. At 6 months' follow-up, ankle-brachial-index, transcutaneous oxygen pressure and maximum walking distance significantly increased, whereas C-reactive protein and interleukin-6 conversely decreased (P < 0.01 versus baseline values), resulting in 88% limb salvage, 75% pain reduction and 71% complete wound healing and/or reduction of ulcer size. One major and one minor amputation were performed, both in patients with Rutherford category 6.ConclusionsAutologous BM-MNC therapy in patients with end-stage PAD improves tissue perfusion indices and decreases markers of inflammation. If our observations could be confirmed by large-scale, randomized controlled trials, BM-MNC transplantation could become an alternative therapeutic option for patients with end-stage PAD.     

Circulating antioxidant vitamins and copper in Azorean coronary artery disease patients under preventive medication – A case study

Background and aimOxidative stress and inflammation are conditions that are deeply involved in atherosclerosis and consequent coronary artery disease (CAD). Therefore, the aim of this study was to assess the relationship among circulating antioxidant vitamins (C, A, E), copper, and other pro- or antioxidant/inflammation markers in patients with and without CAD under preventive medication.Subjects and methods174 Azorean subjects symptomatic for CAD (age 56 ± 9y; 68 % men) submitted to coronary angiography were split into 2 groups: one formed by CAD patients (≥50 % stenosis in at least one major coronary vessel) and the other by non-CAD patients (<50 % stenosis). Both groups were age-, sex- and BMI-matched. Plasma levels of vitamins or copper were measured by HPLC and AAS, respectively.Results and conclusionsLower vitamin C levels were observed in CAD patients (mainly in women, who exhibited a high rate of diabetes mellitus) as compared to the non-CAD ones. Also, CAD patients (mainly men) exhibited significantly higher concentrations of plasma copper than their non-CAD counterparts (1.17 ± 0.3 mg/L vs. 1.09 ± 0.3 mg/L, p = 0.030). In bivariate analysis, plasma copper levels were positively associated with serum LDL-cholesterol (r=0.22; p = 0.004) and chiefly with C-reactive protein (r=0.40; p < 0.001). Furthermore, they were significantly lower in recurrent vs. non recurrent CAD patients (1.07±0.2 vs. 1.24±0.3 mg/L, p = 0.004). ROC analysis showed that plasma copper, whenever >1.06 mg/L, was an independent risk factor for CAD in primary prevention for men, which suggests that its levels can fluctuate with medical therapy (such as anti-inflammatory), thus indicating that copper is not a reliable marker for CAD. Moreover, plasma copper concentration was not associated with CAD severity. Yet, results do suggest that, even within its reference concentration range, it could be useful as an acute inflammation marker in CAD management.     

Hemangiomas - current therapeutic strategies

Hemangiomas are benign neoplasms of the vasculature frequently encountered in children. Several studies have shown that these tumors are characterized by excessive angiogenesis. Although benign, the lesions can present with complications, and may thus require treatment. There are multiple therapeutic options available for patients with problematic or life threatening hemangiomas, some of which have serious side effects. Randomized clinical trials and evidence-based studies on the efficacy of these treatments is still lacking. The recognition that excessive angiogenesis underlies hemangiogenesis offers an opportunity for the development of safer therapeutic strategies that are based on the inhibition of angiogenesis. We review medical therapies currently employed in the management of hemangiomas and the role of angiogenesis inhibition in hemangioma therapy.