Pharmacological revascularisation in coronary and peripheral vascular disease

Therapeutic angiogenesis is a novel approach to the treatment of ischaemic or occlusive coronary and peripheral vascular disease. The therapeutic concept is based on the restoration of distal blood flow by the enlargement of existing vessels and tissue perfusion by the induction of new capillaries. Initial studies have focused on the direct application of endothelial growth factors, vascular endothelial growth factor and fibroblast growth factor, or the delivery of genes using either a plasmid or adenoviral vector. Recently, new angiogenic agents such as hypoxia inducible factor-1alpha, fibroblast growth factor-4, Del-1 and hepatocyte growth factor have entered clinical testing. Moreover, stem-cell therapy or factors mobilising bone marrow progenitor cells have provided evidence for a new avenue for therapeutic angiogenesis. Numerous preclinical studies and several initial clinical trials have provided encouraging data in support of the feasibility of promoting biological revascularisation by the administration of angiogenic factors or cells.     

Gene therapy for coronary and peripheral artery disease

Background: Coronary and peripheral artery diseases are highly prevalent diseases, which are characterised by an unmet medical need in the more advanced stages of disease. These comprise the need for vessel regeneration using therapeutic angiogenic gene therapy as well as the prevention of restenosis post-angioplasty using local gene therapy. Both problems have been addressed by extensive research. Objective: Therefore, this article reviews the patents for therapeutic strategies using gene therapy for the prevention of restenosis and induction of therapeutic angiogenesis in the years 1994 – 2008. Methods: Current publications, websites and patents of a number of potentially suitable gene constructs are reviewed. Conclusion: Cardiovascular gene therapy, particularly in therapeutic angiogenesis, has quietly made its way to the first Phase III approval gene therapy trial. There are chances for more gene constructs to reach this stage.     

Pharmacotherapy for end-stage coronary artery disease

Importance of the field: Coronary artery disease remains the leading cause of mortality in the industrialized world. Despite advances in surgical and catheter-based interventions, a select number of patients remain with no options for invasive therapy. The goal of this review is to discuss the current status of pharmacotherapeutic interventions to treat end-stage coronary artery disease.

Areas covered in this review: Literature review on the topic of therapeutic angiogenesis from 1980 to 2009.

What the reader will gain: Insight into current therapeutic strategies employed to manage end-stage coronary artery disease.

Take home message: A promising approach focuses on augmenting the endogenous angiogenic response to chronic myocardial ischemia via the use of growth factors.     

Effects of vascular endothelial growth factor (VEGF)A and VEGFB gene transfer on vascular reserve in a conscious rabbit hindlimb ischaemia model

1. As a result of the ageing population, there are increasing numbers of patients with severe peripheral vascular occlusive disease associated with intermittent claudication (pain on walking) and decreased exercise tolerance. There is a great clinical need for pharmacological treatments that may stimulate collateral blood vessel growth, increase vascularity and improve skeletal muscle function. 2. Therapeutic angiogenesis using growth factors such as vascular endothelial growth factor (VEGF) has been used to improve collateral artery development in myocardial or skeletal muscle ischaemia. The broad aims of the work briefly summarized here were to compare the effects of VEGFA165 and VEGFB167 (500 micro g, i.m., gene transfer) on calf blood pressure ratio and reactive hyperaemia in a chronic rabbit preparation with unilateral limb ischaemia. 3. Unilateral femoral artery ligation caused an immediate deficit (compared with the contralateral limb) of 72% in calf systolic blood pressure. There were improvements 14 days after ligation with VEGFA and VEGFB treatments compared with the vehicle control plasmid treatment, but a deficit remained of some 32%. 4. Reactive hyperaemic responses were significantly attenuated 7 days after ligation in the vehicle and VEGFA treatment groups. On day 14, this loss of vascular reserve was restored in the VEGFA group, but remained in the vehicle group (-30%). In VEGFB-treated animals, there was no deficit in reserve 7-14 days post-ligation. 5. In conclusion, there is considerable value in the serial measurements of calf blood pressure ratio and reactive hyperaemia in the rabbit unilateral hindlimb ischaemia model. Gene transfer of either VEGFA or VEGFB allowed significant improvements in these indices compared with vehicle but, at 14 days post-ligation, large deficits still remained. Studies extending this experimental period are in progress.     

Therapeutic angiogenesis: protein-based therapy for coronary artery disease

Therapeutic angiogenesis is a promising treatment for ischaemic heart disease, particularly for patients who are not candidates for current methods of revascularisation. The goal of angiogenic therapy is the relief of symptoms of coronary artery disease and improvement of cardiac function by increasing perfusion to the ischaemic myocardium. Angiogenic cytokines such as fibroblast growth factor and vascular endothelial growth factor have been studied extensively in preclinical studies. Protein-based therapy with these growth factors has produced functionally significant angiogenesis in several animal models. Enthusiasm following these preclinical results led the way to clinical trials, which so far have shown only modest improvements in myocardial perfusion and clinical outcome. The attenuated angiogenic response to growth factor therapy observed in patients with coronary artery disease may be related to associated conditions such as endothelial dysfunction, regimens of single as opposed to multiple angiogenic agents and inefficiency of current delivery modalities, as illustrated by the disappointing results of the Phase II clinical trials using intravascular techniques of administration. The ultimate role angiogenesis will play clinically in the treatment of ischaemic heart disease will be determined by adequately powered, randomised, double-blind, placebo-controlled trials that include multi-agent angiogenic therapy and intramyocardial methods of delivery.     

冠心病介入治疗的效果及其对血管内皮生长因子和C-反应蛋白水平的影响

目的 探讨冠心病介入治疗的效果及对血管内皮生长因子（VEGF）和C-反应蛋白（CRP）水平的影响。方法127例心绞痛和心肌梗死患者，行PCI（PTCA／PTCA＋支架术），观察疗效，测定CRP和VEGF在手术前后的变化。结果127例患者共安置支架146枚，支架全部成功地置入靶血管病变部位；有2例双支病变患者因导丝不能通过前降支狭窄部位放弃，4例患者发生无再流现象，手术成功率为95．3％。CRP的水平术后增加142．9％，而VEGF术后减少31．9％。结论PCI对冠心病的治疗效果是满意的，监测血清中CRP和VEGF可了解治疗效果和炎症程度。     

Pigment epithelium-derived factor (PEDF) as a therapeutic target in cardiovascular disease

In this review we discuss the role of pigment epithelium-derived factor (PEDF) as a possible new target molecule to therapeutically influence cardiovascular disease. PEDF is a multifunctional, pleiotropic protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic and neuroprotective properties. First identified in retinal pigment epithelium cells, it is expressed in various tissues throughout the body such as the eye, liver and adipose tissue. Recently PEDF has also been characterized in the heart. PEDF has been suggested to have a protective role in atherosclerosis, the main cause of coronary heart disease, myocardial infarction and heart failure due to its anti-inflammatory, antioxidant and antithrombotic effects in the vessel wall and platelets. Additionally PEDF has strong antiangiogenic effects by inducing apoptosis in endothelial cells and by regulating the expression of other angiogenic factors. Therefore blocking of PEDF locally for example in ischemic tissue in the heart might favour angiogenesis, induce neovascularization and lead to increased perfusion of the injured tissue. On the other hand, local overexpression of PEDF restricted to atherosclerotic lesions might block angiogenesis, inflammation and thrombosis at these sites and thus counteract destabilization and rupture of the lesion otherwise caused by inflammatory activation and excessive angiogenesis and inhibit subsequent thrombus formation.     

Gene therapy for cardiovascular diseases

The advent of gene therapy techniques has made it possible to intervene in cardiovascular diseases by transferring an appropriate therapeutic gene to the relevant cells in humans. A number of preclinical efforts have begun to culminate in clinical studies for life threatening conditions like hypercholesterolaemia and ischaemic vascular disease. Other cardiovascular indications are under investigation, with late stage preclinical studies focusing on restenosis, transplant atherosclerosis and rejection, and various lipoprotein abnormalities. Several recent reviews have outlined the issues surrounding gene therapy in general [1,2]. This review will discuss gene transfer approaches designed specifically to treat diseases of the cardiovascular system, and relevant patents and patent applications.     

Cyclin-dependent protein kinases as therapeutic targets in cardiovascular disease

Excessive cell proliferation is thought to contribute to the development of neointimal lesions during the pathogenesis of atherosclerosis, restenosis and vessel bypass graft failure. Since cell cycle progression requires the sequential activation of cyclin-dependent kinases (CDKs), through their association with regulatory subunits dubbed cyclins, therapeutic strategies via CDK inhibition may reduce the burden of vascular proliferative disease. Some of these approaches may rely on the use of pharmacological CDK inhibitors that target the ATP-binding pocket of the catalytic site of CDK. Others are based on the overexpression of members of the family of CDK inhibitory proteins (CKIs), which associate with and inhibit the activity of CDK/cyclin holoenzymes. In this review, animal studies that document the efficacy of pharmacological agents and gene therapy approaches directly targeting CDK/cyclins for the treatment of vascular proliferative disease are discussed. Recent patent applications in this field are also analysed.     

Association between periodontal disease and coronary artery disease

The etiology of coronary artery disease (CAD) is multifunctional. There is increasing evidence that dental infections could play a role in the initiation and development of CAD. In a case control double blind study, one hundred male and female (mean age 51 ± 9.4) angiographically documented CAD, compared with one hundred male and female patients (mean age 50.6 ± 9) with angiographically negative coronary artery. All the patients (cases and control) underwent dental examination for the presence and severity of periodontitis by a dentist who was oblivious the result of the angiography performed. The association between periodontal disease status and CAD was significant (P=0.011); periodontitis was apparently more frequent in CAD positive patients than in control (86% versus 61%). Adjustment of coronary risk factors (smoking, DM, hypertension and hyperlipidemia) in both cases and control groups suggests that the association between periodontitis and CAD in our study was independent of coronary risk factors. There is increasing evidence that dental infection, especially aerobic organisms which have capability of aggregation of platelets, is the most important cause. Dental infection would be an independent risk factor for CAD.     

踝臂指数评价冠心病患者外周动脉疾病的临床研究

目的观察冠状动脉粥样硬化性心脏病（冠心病）患者合并外周动脉疾病（PAD）的发病情况,探讨踝臂指数（ABI）在临床上的应用价值。方法选取冠心病患者269例,收集相关临床资料并检测相关生化指标,采用科林动脉硬化检测仪测量受试者的ABI值。结果冠心病患者中合并PAD者82例,总患病率为30.5%,女性PAD患病率明显高于男性（36.6%比21.0%,P〈0.01）。PAD组年龄、总胆固醇、缺血性脑卒中显著高于非PAD组（P〈0.05或〈0.01）,多因素Logistic回归分析显示,性别、年龄、总胆固醇及缺血性脑卒中是冠心病患者伴PAD的危险因素。结论 ABI是筛查冠心病患者伴PAD的简单易行又可靠的指标,性别、年龄、总胆固醇及缺血性脑卒中是冠心病患者ABI降低的危险因素。     

Role of peripheral vascular resistance as an indicator of cardiovascular abnormalities in patients with Parkinson's disease

The aim of this study was to evaluate cardiovascular autonomic modulation in response to an orthostatic stress in healthy subjects and Parkinson's disease (PD ). The study included 47 controls and 56 PD patients divided into groups (vasoconstrictor PD , vasodilator PD , control) according to vasodilation/vasoconstriction response during 70° head up tilt test. Using impedance cardiography (ICG ) and electrocardiography (ECG ) we measured stroke volume, cardiac output, left ventricular work index, left ventricular ejection time, acceleration index, index of contractility, Heather index, thoracic fluid content, total peripheral resistance, total arterial compliance. We also analyzed heart rate variability (HRV ), using spectral analysis and continuous blood pressure (contBP). At rest, the vasodilator PD group showed significantly higher values of total peripheral resistance and lower values of stroke volume and cardiac output, compared to the vasoconstrictor PD and the control groups. A post‐tilt drop in ? (change rest – tilt) systolic blood pressure, ?mean blood pressure, ?total peripheral resistance and ?Heather index, and a significantly lower increase in ?diastolic blood pressure was observed in subjects from the vasodilator PD group compared to the vasoconstrictor PD and the control groups. No statistically significant differences were observed for HRV parameters between the vasoconstrictor and vasodilator PD groups, P  > .05. Longer duration and higher disease stage of PD correlated with a reduction in post‐tilt systolic blood pressure changes in vasodilator group. Positive inotropy of the cardiac muscle represents a significant factor preventing orthostatic hypotension in PD subjects with a concurrent drop in peripheral vascular resistance during orthostatic stress.     

Liposome technology for cardiovascular disease treatment and diagnosis

Introduction: Over the past several decades, liposomes have been used in a variety of applications, from delivery vehicles to cell membrane models. In terms of pharmaceutical use, they can offer control over the release of active agents encapsulated into their lipid bilayer or aqueous core, while providing protection from degradation in the body. In addition, liposomes are versatile carriers, because targeting moieties can be conjugated on the surface to enhance delivery efficiency. It is for these reasons that liposomes have been applied as carriers for a multitude of drugs and genetic material, and as contrast agents, aimed to treat and diagnose cardiovascular diseases.

Areas covered: This review details advancements in liposome technology used in the field of cardiovascular medicine. In particular, the application of liposomes to cardiovascular disease treatment and diagnosis, with a focus on delivering drugs, genetic material and improving cardiovascular imaging, will be explored. Advances in targeting liposomes to the vasculature will also be detailed.

Expert opinion: Liposomes may provide the means to deliver drugs and other pharmaceutical agents for cardiovascular applications; however, there is still a vast amount of research and clinical trials that must be performed before a formulation is brought to market. Advancements in targeting abilities within the body, as well as the introduction of theranostic liposomes, capable of both delivering treating and imaging cardiac diseases, may be expected in the future of this burgeoning field.     

Emerging drugs in peripheral arterial disease

Peripheral arterial disease (PAD) is the manifestation of atherosclerotic occlusion within a peripheral vascular bed. This can occur in any noncoronary arterial bed, but PAD most commonly refers to atherosclerosis in the aorto–iliac system and infrainguinal vessels that lead to symptoms in the lower extremities. The disease most often becomes clinically apparent in elderly individuals, commonly presenting as intermittent claudication. More advanced, or multisegmental disease, may present with ischaemic rest pain or tissue loss. Although the limb manifestations of PAD can be disabling, PAD is also a marker of coronary or cerebrovascular atherosclerosis. In fact, ~ 80% of mortality in PAD patients is secondary to a cardiovascular event. In accordance with this, initial medical management of this disease focuses on preventative and risk reduction strategies to minimise the risk of cardiovascular morbidity and mortality. At present, the majority of recommendations with respect to risk reduction therapy in PAD patients are extrapolated from the coronary and cerebrovascular literature. Limb-directed therapy in PAD intends to minimise symptoms and serve as an adjunct to surgical intervention. However, existing data on the efficacy of these agents suggests that they are only partially effective. In addition, the effect of existing nonoperative intervention on the progression of disease has not been completely elucidated. As such, new therapies are under development, which target various goals, including minimising local progression of disease, minimising disability, reducing systemic cardiovascular morbidity/mortality and augmenting the durability of surgical intervention.     

Postmenopausal hormone therapy and the risk of cardiovascular disease

Background: Risks and benefits of postmenopausal hormone therapy remain highly controversial. After publication of the Women's Health Initiative hormone trials and several other major trials, the American Heart Association designated postmenopausal hormone therapy as ‘Class III’, if initiated for the purpose of cardiovascular disease prevention. Subsequent post hoc analyses of the Women's Health Initiative data have renewed enthusiasm for hormone therapy among younger postmenopausal women. Objective: To review data from randomized clinical trials that have assessed cardiovascular outcomes of hormone therapy including coronary heart disease, stroke, peripheral arterial disease, and venous thromboembolism. Methods: The review focuses on cardiovascular effects of hormone therapy only and does not attempt to integrate potential risks and benefits related to symptoms, cancer, osteoporosis or other noncardiovascular effects of postmenopausal hormone therapy. The literature search included original trial publications, post hoc analyses, and aggregate data from meta-analyses published in English and accessible to the author in full-text format for detailed analysis. Results/conclusion: Risks of hormone therapy seem to predominate among older postmenopausal women. Data among younger women close to menopause are insufficient to recommend such therapy for cardiovascular disease prevention.     

血管内皮细胞功能与心血管疾病相关因子研究进展

血管内皮细胞 (VEC)功能与心血管疾病的发生和发展密切相关 ,研究VEC功能与心血管疾病形成之间的相互关系将为心血管疾病的治疗提供新思路、新策略。该文就VEC分泌的活性物质对血管收缩 /舒张功能 ,对血小板粘附、聚集功能的调节 ,对凝血、抗凝及纤溶过程的调节 ,对血管壁修复和重塑的调节等方面进行了综述     

Pharmacological treatment of pediatric Gaucher disease

ABSTRACT

Introduction: Gaucher disease (GD) is an autosomal recessive disorder resulting from the deficiency of the lysosomal enzyme glucocerebrosidase (b-glucosidase), associated with varying degrees of visceral, bone and central nervous system pathology, leading to wide phenotypic diversity. Response to therapy and clinical outcomes are very different between the three clinical subtypes – non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms; hence a definitive clinical diagnosis is essential. The availability of two therapeutic options, i.e. enzyme replacement and substrate reduction, has transformed the natural course of the disease. As pre-treatment disease severity clearly impacts results of therapy, early diagnosis and initiation of treatment especially in the pediatric population are keys to achieving an optimal outcome.

Areas covered: We reviewed the literature concerning the treatment of GD focusing on pediatric presentations, various pharmacological treatment options and recommendations for management goals. A PubMed literature search was performed for relevant publications between 1991 and September 2018.

Expert commentary: The approval of enzyme replacement therapy (ERT) for GD in the pediatric age group has significantly altered the course of the disease, especially for non-neuronopathic and chronic neuronopathic forms, as ERT does not cross the blood-brain barrier. Early diagnosis, regular follow-up and early initiation of treatment can thus prevent some irreversible complications and improve patient quality of life.     

Multi-centre general practitioner trial of isoxsuprine in peripheral vascular disease

Summary

The results of a multi-centre general practitioner trial of isoxsuprine in peripheral vascular disease suggest that continuous treatment with isoxsuprine increases the walking distance of patients with intermittent claudication and improves subjective symptoms. One hundred and forty-nine patients completed the 4-month trial.

A survey of this type of peripheral vascular disease has shown that claudication is a far more frequent symptom than trophic skin lesion. The results of the trial show that where no improvement of claudication distance occurs, then no improvement in subjective symptoms can be expected.